8-22163875-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The NM_001317778.2(SFTPC):c.436-26C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,596,378 control chromosomes in the GnomAD database, including 53,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.28 ( 6156 hom., cov: 33)

Exomes 𝑓: 0.25 ( 47561 hom. )

Consequence

SFTPC
NM_001317778.2 intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.67

Publications

15 publications found

Variant links:

Genes affected

SFTPC (HGNC:10802): (surfactant protein C) This gene encodes the pulmonary-associated surfactant protein C (SPC), an extremely hydrophobic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 2, also called pulmonary alveolar proteinosis due to surfactant protein C deficiency, and are associated with interstitial lung disease in older infants, children, and adults. Alternatively spliced transcript variants encoding different protein isoforms have been identified.[provided by RefSeq, Feb 2010]

SFTPC Gene-Disease associations (from GenCC):

surfactant metabolism dysfunction, pulmonary, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
chronic respiratory distress with surfactant metabolism deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
SFTPC- related interstitial lung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SFTPC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 8-22163875-C-G is Benign according to our data. Variant chr8-22163875-C-G is described in ClinVar as Benign. ClinVar VariationId is 165211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001317778.2 link	c.436-26C>G		intron_variant	Intron 4 of 5	ENST00000679463.1	NP_001304707.1	P11686A0A0A0MTC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1 link	c.436-26C>G		intron_variant	Intron 4 of 5		NM_001317778.2	ENSP00000505152.1		A0A0A0MTC9

Frequencies

GnomAD3 genomes

AF:

0.280

AC:

42620

AN:

152072

Hom.:

6147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.314

Gnomad AMI

AF:

0.182

Gnomad AMR

AF:

0.337

Gnomad ASJ

AF:

0.287

Gnomad EAS

AF:

0.294

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.245

Gnomad OTH

AF:

0.286

GnomAD2 exomes

AF:

0.271

AC:

66639

AN:

245824

AF XY:

0.263

show subpopulations

Gnomad AFR exome

AF:

0.314

Gnomad AMR exome

AF:

0.359

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.296

Gnomad FIN exome

AF:

0.318

Gnomad NFE exome

AF:

0.246

Gnomad OTH exome

AF:

0.270

GnomAD4 exome

AF:

0.254

AC:

366152

AN:

1444188

Hom.:

47561

Cov.:

AF XY:

0.251

AC XY:

180479

AN XY:

719502

show subpopulations

African (AFR)

AF:

0.314

AC:

10416

AN:

33164

American (AMR)

AF:

0.361

AC:

16128

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6938

AN:

26022

East Asian (EAS)

AF:

0.332

AC:

13165

AN:

39622

South Asian (SAS)

AF:

0.191

AC:

16378

AN:

85910

European-Finnish (FIN)

AF:

0.317

AC:

16801

AN:

53080

Middle Eastern (MID)

AF:

0.299

AC:

1720

AN:

5744

European-Non Finnish (NFE)

AF:

0.245

AC:

269006

AN:

1096232

Other (OTH)

AF:

0.261

AC:

15600

AN:

59760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

14115

28230

42344

56459

70574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9220

18440

27660

36880

46100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.280

AC:

42654

AN:

152190

Hom.:

6156

Cov.:

AF XY:

0.284

AC XY:

21105

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.314

AC:

13022

AN:

41520

American (AMR)

AF:

0.337

AC:

5155

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

996

AN:

3470

East Asian (EAS)

AF:

0.293

AC:

1514

AN:

5176

South Asian (SAS)

AF:

0.202

AC:

975

AN:

4832

European-Finnish (FIN)

AF:

0.331

AC:

3504

AN:

10592

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.245

AC:

16628

AN:

67994

Other (OTH)

AF:

0.286

AC:

604

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1633

3265

4898

6530

8163

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.258

Hom.:

1767

Bravo

AF:

0.283

Asia WGS

AF:

0.254

AC:

883

AN:

3478

EpiCase

AF:

0.243

EpiControl

AF:

0.247

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

436-8C>G in intron 4 of SFTPC: This variant is not expected to have clinical sig nificance because it has been identified in 29.9% (1206/4034) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2070687). -

Interstitial lung disease 2

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis Imperfecta, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pulmonary Surfactant Metabolism Dysfunction, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Surfactant metabolism dysfunction, pulmonary, 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

(source)

DANN

Benign

0.57

PhyloP100

1.7

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.54

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.54

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over