chr19-36146216-C-T

Position:

• chr19-36146216-C-T

Variant summary

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

The NM_001749.4(CAPNS1):​c.625C>T​(p.Leu209Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CAPNS1 NM_001749.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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.625C>T	p.Leu209Phe	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.625C>T	p.Leu209Phe	missense_variant	9/11	1	NM_001749.4	ENSP00000246533	P1
	ENST00000604228.1	n.310+1823G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460730 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726756

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Jul 12, 2023

The c.625C>T (p.L209F) alteration is located in exon 9 (coding exon 8) of the CAPNS1 gene. This alteration results from a C to T substitution at nucleotide position 625, causing the leucine (L) at amino acid position 209 to be replaced by a phenylalanine (F). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;T;T;T;.;T;D;T;T;T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	.;.;T;T;T;.;T;.;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.014	D;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;T;T
Polyphen		0.76	P;.;.;.;.;.;P;.;.;.;.
Vest4		0.41
MutPred		0.53		Loss of stability (P = 0.2657);.;.;.;Loss of stability (P = 0.2657);.;Loss of stability (P = 0.2657);.;.;.;.;
MVP		0.93
MPC		0.69
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.74
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: chr19-36637118;