5-96765320-G-T

Variant names:

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

Variant summary

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

The NM_001750.7(CAST):​c.2032G>T​(p.Val678Leu) variant causes a missense change. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0038 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Uncertain_significance. The variant received 0 ACMG points.

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>T	p.Val678Leu	missense	Exon 26 of 32	NP_001741.4
	CAST	NM_001042441.3		c.1975G>T	p.Val659Leu	missense	Exon 25 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.1966G>T	p.Val656Leu	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>T	p.Val678Leu	missense	Exon 26 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1783G>T	p.Val595Leu	missense	Exon 24 of 30	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.1744G>T	p.Val582Leu	missense	Exon 25 of 31	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.000265 AC: 9 AN: 33982 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00152

Gnomad SAS AF: 0.000873

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000227

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00383 AC: 1272 AN: 331936 Hom.: 0 Cov.: 9 AF XY: 0.00333 AC XY: 610 AN XY: 183154

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

African (AFR) AF: 0.00246 AC: 17 AN: 6912

American (AMR) AF: 0.000228 AC: 4 AN: 17552

Ashkenazi Jewish (ASJ) AF: 0.00109 AC: 10 AN: 9134

East Asian (EAS) AF: 0.00136 AC: 20 AN: 14678

South Asian (SAS) AF: 0.000741 AC: 23 AN: 31030

European-Finnish (FIN) AF: 0.000728 AC: 23 AN: 31572

Middle Eastern (MID) AF: 0.00429 AC: 5 AN: 1166

European-Non Finnish (NFE) AF: 0.00549 AC: 1127 AN: 205176

Other (OTH) AF: 0.00292 AC: 43 AN: 14716

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000264 AC: 9 AN: 34030 Hom.: 0 Cov.: 0 AF XY: 0.000384 AC XY: 6 AN XY: 15640

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

African (AFR) AF: 0.00 AC: 0 AN: 9088

American (AMR) AF: 0.000438 AC: 1 AN: 2284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1140

East Asian (EAS) AF: 0.00153 AC: 2 AN: 1308

South Asian (SAS) AF: 0.000873 AC: 1 AN: 1146

European-Finnish (FIN) AF: 0.00123 AC: 1 AN: 812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 48

European-Non Finnish (NFE) AF: 0.000227 AC: 4 AN: 17592

Other (OTH) AF: 0.00 AC: 0 AN: 448

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000171552), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.46
MutPred		0.50		Loss of methylation at K655 (P = 0.0354)
MVP		0.74
MPC		0.12
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.29
gMVP		0.093
Mutation Taster		=74/26	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;