chr8-22163947-G-A

Variant names:

• chr8-22163947-G-A
• rs34957318
• NM_001317778.2:c.482G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001317778.2(SFTPC):​c.482G>A​(p.Arg161Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,613,684 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 34)
  • Exomes 𝑓: 0.00043 (9 hom.)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8
• Conservation: PhyloP100: -2.61
• Publications: 22 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053222448).
• BP6: Variant 8-22163947-G-A is Benign according to our data. Variant chr8-22163947-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13209.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00414 (631/152400) while in subpopulation AFR AF = 0.0144 (600/41594). AF 95% confidence interval is 0.0135. There are 5 homozygotes in GnomAd4. There are 297 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 631 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317778.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPC	NM_001317778.2	MANE Select	c.482G>A	p.Arg161Gln	missense	Exon 5 of 6	NP_001304707.1	P11686-2
	SFTPC	NM_001172410.2		c.500G>A	p.Arg167Gln	missense	Exon 5 of 6	NP_001165881.1	A0A0S2Z4Q0
	SFTPC	NM_001385653.1		c.500G>A	p.Arg167Gln	missense	Exon 5 of 6	NP_001372582.1	P11686-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPC	ENST00000679463.1	MANE Select	c.482G>A	p.Arg161Gln	missense	Exon 5 of 6	ENSP00000505152.1	P11686-2
	SFTPC	ENST00000318561.7	TSL:1	c.500G>A	p.Arg167Gln	missense	Exon 5 of 6	ENSP00000316152.3	P11686-1
	SFTPC	ENST00000521315.5	TSL:1	c.482G>A	p.Arg161Gln	missense	Exon 5 of 5	ENSP00000430410.1	P11686-2

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 628 AN: 152282 Hom.: 5 Cov.: 34

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00110 AC: 274 AN: 248666 AF XY: 0.000762

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000430 AC: 629 AN: 1461284 Hom.: 9 Cov.: 33 AF XY: 0.000330 AC XY: 240 AN XY: 726954

African (AFR) AF: 0.0152 AC: 508 AN: 33474

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1112000

Other (OTH) AF: 0.000961 AC: 58 AN: 60358

GnomAD4 genome AF: 0.00414 AC: 631 AN: 152400 Hom.: 5 Cov.: 34 AF XY: 0.00399 AC XY: 297 AN XY: 74524

African (AFR) AF: 0.0144 AC: 600 AN: 41594

American (AMR) AF: 0.00131 AC: 20 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00144 Hom.: 2

Bravo AF: 0.00475

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0149 AC: 61

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	2	Surfactant metabolism dysfunction, pulmonary, 2 (3)
-	1	1	Interstitial lung disease 2 (2)
-	-	2	not provided (2)
-	-	1	Hereditary pulmonary alveolar proteinosis (1)
-	-	1	not specified (1)
-	-	1	SFTPC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.0040
DANN	Benign	0.88
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.89	T
PhyloP100		-2.6
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.28
Sift	Benign	0.16	T
Sift4G	Benign	0.32	T
Vest4		0.075
MVP		0.36
MPC		0.58
ClinPred		0.0086	T
GERP RS		-11
gMVP		0.53
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34957318; hg19: chr8-22021460; COSMIC: COSV105876885; COSMIC: COSV105876885;