19-36146220-A-G

Position:

• chr19-36146220-A-G

Variant summary

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

The NM_001749.4(CAPNS1):​c.629A>G​(p.Tyr210Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPNS1 NM_001749.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.631

Genes affected

CAPNS1 (HGNC:1481): (calpain small subunit 1) This gene is a member of the calpain small subunit family. Calpains are calcium-dependent cysteine proteinases that are widely distributed in mammalian cells. Calpains operate as heterodimers, comprising a specific large catalytic subunit (calpain 1 subunit in Calpain I, and calpain 2 subunit in Calpain II), and a common small regulatory subunit encoded by this gene. This encoded protein is essential for the stability and function of both calpain heterodimers, whose proteolytic activities influence various cellular functions including apoptosis, proliferation, migration, adhesion, and autophagy. Calpains have been implicated in neurodegenerative processes, such as myotonic dystrophy. A pseudogene of this gene has been defined on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

(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
CAPNS1	NM_001749.4	c.629A>G	p.Tyr210Cys	missense_variant	9/11	ENST00000246533.8	NP_001740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPNS1	ENST00000246533.8	c.629A>G	p.Tyr210Cys	missense_variant	9/11	1	NM_001749.4	ENSP00000246533	P1
	ENST00000604228.1	n.310+1819T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.629A>G (p.Y210C) alteration is located in exon 9 (coding exon 8) of the CAPNS1 gene. This alteration results from a A to G substitution at nucleotide position 629, causing the tyrosine (Y) at amino acid position 210 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;T;T;T;.;T;D;T;T;T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	.;.;D;D;D;.;D;.;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.7	D;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.029	D;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.67	P;.;.;.;.;.;P;.;.;.;.
Vest4		0.50
MutPred		0.43		Loss of catalytic residue at L205 (P = 0.1449);.;.;.;Loss of catalytic residue at L205 (P = 0.1449);.;Loss of catalytic residue at L205 (P = 0.1449);.;.;.;.;
MVP		0.96
MPC		0.67
ClinPred		0.90	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.85
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36637122;