chr2-240591938-A-G

Position:

• chr2-240591938-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_023083.4(CAPN10):​c.476A>G​(p.His159Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,460,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CAPN10 NM_023083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

Genes affected

CAPN10 (HGNC:1477): (calpain 10) Calpains represent a ubiquitous, well-conserved family of calcium-dependent cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large catalytic subunit has four domains: domain I, the N-terminal regulatory domain that is processed upon calpain activation; domain II, the protease domain; domain III, a linker domain of unknown function; and domain IV, the calmodulin-like calcium-binding domain. This gene encodes a large subunit. It is an atypical calpain in that it lacks the calmodulin-like calcium-binding domain and instead has a divergent C-terminal domain. It is similar in organization to calpains 5 and 6. This gene is associated with type 2 or non-insulin-dependent diabetes mellitus (NIDDM), and is located within the NIDDM1 region. Multiple alternative transcript variants have been described for this gene. [provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN10	NM_023083.4	c.476A>G	p.His159Arg	missense_variant	4/12	ENST00000391984.7	NP_075571.2
CAPN10	NM_023085.4	c.476A>G	p.His159Arg	missense_variant	4/10		NP_075573.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN10	ENST00000391984.7	c.476A>G	p.His159Arg	missense_variant	4/12	1	NM_023083.4	ENSP00000375844	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460540 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726456

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.476A>G (p.H159R) alteration is located in exon 4 (coding exon 4) of the CAPN10 gene. This alteration results from a A to G substitution at nucleotide position 476, causing the histidine (H) at amino acid position 159 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M;.;M;.
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D;D;D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0090	D;D;D;.
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.59	P;P;P;.
Vest4		0.30
MVP		0.93
MPC		0.61
ClinPred		0.89	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.84

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: rs368964748; hg19: chr2-241531355;