NM_001143962.2:c.734C>A

Variant names:

• chr1-223625884-G-T
• rs35539373
• NM_001143962.2:c.734C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001143962.2(CAPN8):​c.734C>A​(p.Ser245Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.553 in 1,549,168 control chromosomes in the GnomAD database, including 239,331 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.57 (25373 hom., cov: 32)
  • Exomes 𝑓: 0.55 (213958 hom.)
• Consequence: CAPN8 NM_001143962.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.00
• Publications: 23 publications found

Genes affected

CAPN8 (HGNC:1485): (calpain 8) Predicted to enable calcium-dependent cysteine-type endopeptidase activity and identical protein binding activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within calcium-dependent self proteolysis. Predicted to be located in Golgi apparatus. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.118681E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143962.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN8	NM_001143962.2	MANE Select	c.734C>A	p.Ser245Tyr	missense	Exon 6 of 21	NP_001137434.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN8	ENST00000366872.10	TSL:1 MANE Select	c.734C>A	p.Ser245Tyr	missense	Exon 6 of 21	ENSP00000355837.6
	CAPN8	ENST00000366873.6	TSL:5	c.734C>A	p.Ser245Tyr	missense	Exon 6 of 10	ENSP00000355838.2
	CAPN8	ENST00000465098.1	TSL:3	c.350C>A	p.Ser117Tyr	missense	Exon 4 of 5	ENSP00000435953.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86835 AN: 151904 Hom.: 25342 Cov.: 32

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.571

GnomAD2 exomes AF: 0.556 AC: 87136 AN: 156664 AF XY: 0.562

Gnomad AFR exome AF: 0.656

Gnomad AMR exome AF: 0.528

Gnomad ASJ exome AF: 0.622

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.543

Gnomad OTH exome AF: 0.549

GnomAD4 exome AF: 0.551 AC: 769220 AN: 1397146 Hom.: 213958 Cov.: 36 AF XY: 0.554 AC XY: 381548 AN XY: 689004

African (AFR) AF: 0.648 AC: 20466 AN: 31566

American (AMR) AF: 0.528 AC: 18842 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 15517 AN: 25166

East Asian (EAS) AF: 0.629 AC: 22449 AN: 35696

South Asian (SAS) AF: 0.648 AC: 51276 AN: 79176

European-Finnish (FIN) AF: 0.420 AC: 20696 AN: 49240

Middle Eastern (MID) AF: 0.542 AC: 3085 AN: 5692

European-Non Finnish (NFE) AF: 0.543 AC: 584639 AN: 1077030

Other (OTH) AF: 0.557 AC: 32250 AN: 57896

GnomAD4 genome AF: 0.572 AC: 86923 AN: 152022 Hom.: 25373 Cov.: 32 AF XY: 0.567 AC XY: 42129 AN XY: 74282

African (AFR) AF: 0.655 AC: 27160 AN: 41444

American (AMR) AF: 0.547 AC: 8357 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2103 AN: 3470

East Asian (EAS) AF: 0.619 AC: 3197 AN: 5166

South Asian (SAS) AF: 0.645 AC: 3100 AN: 4808

European-Finnish (FIN) AF: 0.408 AC: 4316 AN: 10574

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36846 AN: 67956

Other (OTH) AF: 0.569 AC: 1201 AN: 2112

Alfa AF: 0.555 Hom.: 47635

Bravo AF: 0.583

TwinsUK AF: 0.528 AC: 1956

ALSPAC AF: 0.543 AC: 2094

ESP6500AA AF: 0.663 AC: 918

ESP6500EA AF: 0.543 AC: 1729

ExAC AF: 0.561 AC: 13817

Asia WGS AF: 0.602 AC: 2096 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.00041	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		8.0
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.20
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.084
MPC		0.0022
ClinPred		0.0095	T
GERP RS		4.4
Varity_R		0.45
gMVP		0.50
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35539373; hg19: chr1-223813586; COSMIC: COSV64817589; COSMIC: COSV64817589;