rs1769477983

Variant names:

• chr5-96765320-G-A
• rs1769477983
• NM_001750.7:c.2032G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-96765320-G-A
• chr5-96765320-G-C
• chr5-96765320-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001750.7(CAST):​c.2032G>A​(p.Val678Ile) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V678L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: CAST NM_001750.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.88
• Publications: 0 publications found

Genes affected

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

CAST (HGNC:):

ERAP1 (HGNC:18173): (endoplasmic reticulum aminopeptidase 1) The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28347582).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. 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
	CAST	NM_001750.7	MANE Select	c.2032G>A	p.Val678Ile	missense	Exon 26 of 32	NP_001741.4
	CAST	NM_001042441.3		c.1975G>A	p.Val659Ile	missense	Exon 25 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.1966G>A	p.Val656Ile	missense	Exon 25 of 31	NP_001035907.1	P20810-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.2032G>A	p.Val678Ile	missense	Exon 26 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1783G>A	p.Val595Ile	missense	Exon 24 of 30	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.1744G>A	p.Val582Ile	missense	Exon 25 of 31	ENSP00000343421.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000300 AC: 1 AN: 332900 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 183660

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6930

American (AMR) AF: 0.00 AC: 0 AN: 17570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9154

East Asian (EAS) AF: 0.00 AC: 0 AN: 14716

South Asian (SAS) AF: 0.00 AC: 0 AN: 31054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1168

European-Non Finnish (NFE) AF: 0.00000486 AC: 1 AN: 205928

Other (OTH) AF: 0.00 AC: 0 AN: 14768

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.097
Sift	Uncertain	0.022	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.26
MutPred		0.52		Loss of methylation at K657 (P = 0.0568)
MVP		0.66
MPC		0.042
ClinPred		0.72	D
GERP RS		4.9
Varity_R		0.092
gMVP		0.056
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs1769477983; hg19: chr5-96101024;