1-223545289-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001143962.2(CAPN8):​c.1775C>A​(p.Thr592Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,318 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAPN8 NM_001143962.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity CAN8_HUMAN
• PM2: Very rare variant in population databases, with high coverage

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>A	p.Thr592Lys	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>A	p.Thr592Lys	missense	Exon 17 of 21	ENSP00000355837.6	A6NHC0
	CAPN8	ENST00000871507.1		c.1763C>A	p.Thr588Lys	missense	Exon 16 of 20	ENSP00000541566.1
	CAPN8	ENST00000961029.1		c.1642-439C>A		intron	N/A	ENSP00000631088.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399318 Hom.: 0 Cov.: 61 AF XY: 0.00 AC XY: 0 AN XY: 690178

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078900

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0025	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.089
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.3
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.24
MutPred		0.58		Gain of ubiquitination at T592 (P = 0.0109)
MVP		0.49
MPC		0.0017
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.029
gMVP		0.57
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61823553; hg19: chr1-223718651;