Genetic Variant SFTPC:c.-92C>G (chr8-22161737-C-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000318561.7(SFTPC):c.-92C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00985 in 1,612,552 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0067 ( 8 hom., cov: 32)

Exomes 𝑓: 0.010 ( 114 hom. )

Consequence

SFTPC
ENST00000318561.7 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.0580

Publications

2 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):

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 8-22161737-C-G is Benign according to our data. Variant chr8-22161737-C-G is described in ClinVar as Benign. ClinVar VariationId is 362545.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00668 (1017/152268) while in subpopulation NFE AF = 0.0108 (734/68020). AF 95% confidence interval is 0.0101. There are 8 homozygotes in GnomAd4. There are 444 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1017 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000318561.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
SFTPC	NM_001385654.1	c.-53-39C>G	intron	N/A	NP_001372583.1	A0A0S2Z4Q0
SFTPC	NM_001385655.1	c.-53-39C>G	intron	N/A	NP_001372584.1	A0A0S2Z4Q0
SFTPC	NM_001385656.1	c.-53-39C>G	intron	N/A	NP_001372585.1	P11686-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SFTPC	ENST00000318561.7	TSL:1	c.-92C>G	5_prime_UTR	Exon 1 of 6	ENSP00000316152.3	P11686-1
SFTPC	ENST00000950317.1		c.-92C>G	5_prime_UTR	Exon 1 of 4	ENSP00000620376.1
SFTPC	ENST00000905727.1		c.-92C>G	5_prime_UTR	Exon 1 of 4	ENSP00000575786.1

Frequencies

GnomAD3 genomes

AF:

0.00668

AC:

1017

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00877

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00698

AC:

1734

AN:

248522

AF XY:

0.00674

show subpopulations

Gnomad AFR exome

AF:

0.00207

Gnomad AMR exome

AF:

0.00759

Gnomad ASJ exome

AF:

0.00845

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00168

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00893

GnomAD4 exome

AF:

0.0102

AC:

14859

AN:

1460284

Hom.:

114

Cov.:

AF XY:

0.00998

AC XY:

7251

AN XY:

726332

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33456

American (AMR)

AF:

0.00792

AC:

354

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00934

AC:

244

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00166

AC:

143

AN:

86132

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

52758

Middle Eastern (MID)

AF:

0.00214

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.0121

AC:

13475

AN:

1111534

Other (OTH)

AF:

0.00821

AC:

495

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

762

1524

2285

3047

3809

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.00668

AC:

1017

AN:

152268

Hom.:

Cov.:

AF XY:

0.00596

AC XY:

444

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41556

American (AMR)

AF:

0.00876

AC:

134

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0108

AC:

734

AN:

68020

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00809

Hom.:

Bravo

AF:

0.00763

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Interstitial lung disease 2 (1)

Surfactant metabolism dysfunction, pulmonary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

4.5

(source)

DANN

Benign

0.66

PhyloP100

0.058

PromoterAI

-0.0040

Neutral

(source)

Mutation Taster

=297/3

polymorphism

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over