12-7062503-T-C

Position:

• chr12-7062503-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001734.5(C1S):​c.34T>C​(p.Trp12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: C1S NM_001734.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.994

Genes affected

C1S (HGNC:1247): (complement C1s) This gene encodes a serine protease, which is a major constituent of the human complement subcomponent C1. C1s associates with two other complement components C1r and C1q in order to yield the first component of the serum complement system. Defects in this gene are the cause of selective C1s deficiency. [provided by RefSeq, Mar 2009]

C1S (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1S	NM_001734.5	c.34T>C	p.Trp12Arg	missense_variant	3/12	ENST00000360817.10	NP_001725.1
C1S	NM_201442.4	c.34T>C	p.Trp12Arg	missense_variant	3/12		NP_958850.1
C1S	NM_001346850.2	c.-288-387T>C		intron_variant			NP_001333779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1S	ENST00000360817.10	c.34T>C	p.Trp12Arg	missense_variant	3/12	1	NM_001734.5	ENSP00000354057.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461214 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Hereditary angioedema with normal C1Inh Other:1

not provided, no classification provided

literature only

CeMIA

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.12	T;T;T;.;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.38	.;.;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.4	L;L;L;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N;N;N;D;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.40	T;T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T;T
Polyphen		0.075	B;B;B;.;.;.
Vest4		0.46
MutPred		0.74		Loss of catalytic residue at L10 (P = 0.0057);Loss of catalytic residue at L10 (P = 0.0057);Loss of catalytic residue at L10 (P = 0.0057);Loss of catalytic residue at L10 (P = 0.0057);Loss of catalytic residue at L10 (P = 0.0057);Loss of catalytic residue at L10 (P = 0.0057);
MVP		0.86
MPC		0.39
ClinPred		0.052	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1591575004; hg19: chr12-7169807;