NM_001750.7:c.2032G>C

Variant names:

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

Variant summary

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

The NM_001750.7(CAST):​c.2032G>C​(p.Val678Leu) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000051 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CAST NM_001750.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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>C	p.Val678Leu	missense	Exon 26 of 32	NP_001741.4
	CAST	NM_001042441.3		c.1975G>C	p.Val659Leu	missense	Exon 25 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.1966G>C	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>C	p.Val678Leu	missense	Exon 26 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1783G>C	p.Val595Leu	missense	Exon 24 of 30	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.1744G>C	p.Val582Leu	missense	Exon 25 of 31	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 33998 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000511 AC: 17 AN: 332886 Hom.: 0 Cov.: 9 AF XY: 0.0000490 AC XY: 9 AN XY: 183648

⚠️ 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: 0.0000569 AC: 1 AN: 17570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9152

East Asian (EAS) AF: 0.00 AC: 0 AN: 14714

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

European-Finnish (FIN) AF: 0.0000633 AC: 2 AN: 31608

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

European-Non Finnish (NFE) AF: 0.0000680 AC: 14 AN: 205922

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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 33998 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 15610

African (AFR) AF: 0.00 AC: 0 AN: 9056

American (AMR) AF: 0.00 AC: 0 AN: 2282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 1314

South Asian (SAS) AF: 0.00 AC: 0 AN: 1150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 46

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 17590

Other (OTH) AF: 0.00 AC: 0 AN: 440

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

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	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.50	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;