rs61823553

Variant names:

• chr1-223545289-G-A
• rs61823553
• NM_001143962.2:c.1775C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-223545289-G-A
• chr1-223545289-G-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BA1

The NM_001143962.2(CAPN8):​c.1775C>T​(p.Thr592Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,550,914 control chromosomes in the GnomAD database, including 213,191 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 0.47 (17754 hom., cov: 32)
  • Exomes 𝑓: 0.53 (195437 hom.)
• Consequence: CAPN8 NM_001143962.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 18 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 -10 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CAN8_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=5.6138635E-4).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.553 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN8	NM_001143962.2	MANE Select	c.1775C>T	p.Thr592Met	missense	Exon 17 of 21	NP_001137434.1	A6NHC0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN8	ENST00000366872.10	TSL:1 MANE Select	c.1775C>T	p.Thr592Met	missense	Exon 17 of 21	ENSP00000355837.6	A6NHC0
	CAPN8	ENST00000871507.1		c.1763C>T	p.Thr588Met	missense	Exon 16 of 20	ENSP00000541566.1
	CAPN8	ENST00000961029.1		c.1642-439C>T		intron	N/A	ENSP00000631088.1

Frequencies

GnomAD3 genomes AF: 0.467 AC: 70964 AN: 151906 Hom.: 17749 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.531

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.543

Gnomad OTH AF: 0.487

GnomAD2 exomes AF: 0.534 AC: 83565 AN: 156486 AF XY: 0.529

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.587

Gnomad EAS exome AF: 0.527

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.545

Gnomad OTH exome AF: 0.530

GnomAD4 exome AF: 0.527 AC: 736533 AN: 1398890 Hom.: 195437 Cov.: 61 AF XY: 0.527 AC XY: 363576 AN XY: 689998

African (AFR) AF: 0.266 AC: 8394 AN: 31590

American (AMR) AF: 0.606 AC: 21632 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 14797 AN: 25178

East Asian (EAS) AF: 0.514 AC: 18365 AN: 35736

South Asian (SAS) AF: 0.488 AC: 38657 AN: 79230

European-Finnish (FIN) AF: 0.544 AC: 26818 AN: 49256

Middle Eastern (MID) AF: 0.535 AC: 3046 AN: 5698

European-Non Finnish (NFE) AF: 0.534 AC: 575494 AN: 1078524

Other (OTH) AF: 0.506 AC: 29330 AN: 57976

GnomAD4 genome AF: 0.467 AC: 71000 AN: 152024 Hom.: 17754 Cov.: 32 AF XY: 0.469 AC XY: 34819 AN XY: 74298

African (AFR) AF: 0.267 AC: 11085 AN: 41472

American (AMR) AF: 0.563 AC: 8604 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2011 AN: 3472

East Asian (EAS) AF: 0.531 AC: 2746 AN: 5170

South Asian (SAS) AF: 0.476 AC: 2289 AN: 4810

European-Finnish (FIN) AF: 0.551 AC: 5810 AN: 10552

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.543 AC: 36890 AN: 67950

Other (OTH) AF: 0.487 AC: 1028 AN: 2112

Alfa AF: 0.512 Hom.: 34298

Bravo AF: 0.462

TwinsUK AF: 0.530 AC: 1967

ALSPAC AF: 0.531 AC: 2047

ESP6500AA AF: 0.252 AC: 349

ESP6500EA AF: 0.545 AC: 1733

ExAC AF: 0.486 AC: 11544

Asia WGS AF: 0.451 AC: 1569 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.13
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.00056	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.3
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.061
MPC		0.0019
ClinPred		0.037	T
GERP RS		3.5
Varity_R		0.018
gMVP		0.40
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs61823553; hg19: chr1-223718651; COSMIC: COSV64814534; COSMIC: COSV64814534;