8-22163947-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001317778.2(SFTPC):​c.482G>C​(p.Arg161Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.61
• Publications: 0 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):

• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11162275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001317778.2	c.482G>C	p.Arg161Pro	missense_variant	Exon 5 of 6	ENST00000679463.1	NP_001304707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1	c.482G>C	p.Arg161Pro	missense_variant	Exon 5 of 6		NM_001317778.2	ENSP00000505152.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	0.0020
DANN	Benign	0.70
DEOGEN2	Benign	0.065	T;T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.50	T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.87	T
PhyloP100		-2.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.17	T;T;T;T
Sift4G	Benign	0.13	T;T;T;T
Vest4		0.14
MutPred		0.56		Gain of loop (P = 0.0079);.;.;.;
MVP		0.38
MPC		0.64
ClinPred		0.058	T
GERP RS		-11
gMVP		0.65
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;