rs2070687

Positions:

chr8-22163875-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBA1

The ENST00000318561.7(SFTPC):c.436-8C>G variant causes a splice region, splice polypyrimidine tract, 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6156 hom., cov: 33)

Exomes 𝑓: 0.25 ( 47561 hom. )

Consequence

SFTPC
ENST00000318561.7 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

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

Conservation

PhyloP100: 1.67

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PP3

Splicing scoreres supports a deletorius 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 id 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/exons	MANE	Protein	UniProt
SFTPC	NM_001317778.2 linkuse as main transcript	c.436-26C>G		intron_variant		ENST00000679463.1	NP_001304707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1 linkuse as main transcript	c.436-26C>G		intron_variant			NM_001317778.2	ENSP00000505152	A1

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

GnomAD3 exomes

AF:

0.271

AC:

66639

AN:

245824

Hom.:

9407

AF XY:

0.263

AC XY:

35132

AN XY:

133744

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 SAS exome

AF:

0.193

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

Gnomad4 AFR exome

AF:

0.314

Gnomad4 AMR exome

AF:

0.361

Gnomad4 ASJ exome

AF:

0.267

Gnomad4 EAS exome

AF:

0.332

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.317

Gnomad4 NFE exome

AF:

0.245

Gnomad4 OTH exome

AF:

0.261

GnomAD4 genome

AF:

0.280

AC:

42654

AN:

152190

Hom.:

6156

Cov.:

AF XY:

0.284

AC XY:

21105

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.314

Gnomad4 AMR

AF:

0.337

Gnomad4 ASJ

AF:

0.287

Gnomad4 EAS

AF:

0.293

Gnomad4 SAS

AF:

0.202

Gnomad4 FIN

AF:

0.331

Gnomad4 NFE

AF:

0.245

Gnomad4 OTH

AF:

0.286

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Interstitial lung disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pulmonary Surfactant Metabolism Dysfunction, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Osteogenesis Imperfecta, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Surfactant metabolism dysfunction, pulmonary, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

DANN

Benign

0.57

BranchPoint Hunter

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over