8-22162646-G-T

Variant names:

• chr8-22162646-G-T
• rs183533911
• NM_001317778.2:c.115G>T

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.115G>T​(p.Val39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,608,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V39M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.0530
• Publications: 15 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=0.013790548).
• BP6: Variant 8-22162646-G-T is Benign according to our data. Variant chr8-22162646-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225466.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00025 (38/152236) while in subpopulation EAS AF = 0.00618 (32/5182). AF 95% confidence interval is 0.00449. There are 1 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 38 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.115G>T	p.Val39Leu	missense	Exon 2 of 6	NP_001304707.1	P11686-2
	SFTPC	NM_001172410.2		c.115G>T	p.Val39Leu	missense	Exon 2 of 6	NP_001165881.1	A0A0S2Z4Q0
	SFTPC	NM_001385653.1		c.115G>T	p.Val39Leu	missense	Exon 2 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.115G>T	p.Val39Leu	missense	Exon 2 of 6	ENSP00000505152.1	P11686-2
	SFTPC	ENST00000318561.7	TSL:1	c.115G>T	p.Val39Leu	missense	Exon 2 of 6	ENSP00000316152.3	P11686-1
	SFTPC	ENST00000521315.5	TSL:1	c.115G>T	p.Val39Leu	missense	Exon 2 of 5	ENSP00000430410.1	P11686-2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152118 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000586 AC: 146 AN: 249328 AF XY: 0.000495

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00695

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000313 AC: 456 AN: 1456474 Hom.: 0 Cov.: 37 AF XY: 0.000328 AC XY: 238 AN XY: 724672

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00866 AC: 343 AN: 39608

South Asian (SAS) AF: 0.000790 AC: 68 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1107658

Other (OTH) AF: 0.000432 AC: 26 AN: 60180

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152236 Hom.: 1 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

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

East Asian (EAS) AF: 0.00618 AC: 32 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000437 Hom.: 0

Bravo AF: 0.000329

ExAC AF: 0.000620 AC: 75

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	-0.18	T
PhyloP100		0.053
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.72
Sift	Benign	0.079	T
Sift4G	Benign	0.098	T
Polyphen		0.015	B
Vest4		0.49
MutPred		0.74		Loss of catalytic residue at V39 (P = 0.0109)
MVP		0.89
MPC		0.47
ClinPred		0.018	T
GERP RS		0.92
gMVP		0.76
Mutation Taster		=11/89	disease causing

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: rs183533911; hg19: chr8-22020159; COSMIC: COSV59346289; COSMIC: COSV59346289;