rs79647630

Variant names:

• chr8-22161737-C-G
• rs79647630
• ENST00000318561:c.-92C>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000318561(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 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0580

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1017 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001385654.1	c.-53-39C>G		intron_variant	Intron 2 of 7		NP_001372583.1
SFTPC	NM_001385655.1	c.-53-39C>G		intron_variant	Intron 2 of 7		NP_001372584.1
SFTPC	NM_001385656.1	c.-53-39C>G		intron_variant	Intron 2 of 6		NP_001372585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000318561	c.-92C>G		5_prime_UTR_variant	Exon 1 of 6	1		ENSP00000316152.3
SFTPC	ENST00000524318.3	n.740-39C>G		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1017 AN: 152150 Hom.: 8 Cov.: 32

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

GnomAD3 exomes AF: 0.00698 AC: 1734 AN: 248522 Hom.: 12 AF XY: 0.00674 AC XY: 908 AN XY: 134794

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 SAS exome AF: 0.00141

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.: 32 AF XY: 0.00998 AC XY: 7251 AN XY: 726332

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00792

Gnomad4 ASJ exome AF: 0.00934

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00166

Gnomad4 FIN exome AF: 0.00136

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.00821

GnomAD4 genome AF: 0.00668 AC: 1017 AN: 152268 Hom.: 8 Cov.: 32 AF XY: 0.00596 AC XY: 444 AN XY: 74442

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00809 Hom.: 1

Bravo AF: 0.00763

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Interstitial lung disease 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. -

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	-0.72
CADD	Benign	4.5
DANN	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs79647630; hg19: chr8-22019250;