5-96774231-T-G

Position:

• chr5-96774231-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001750.7(CAST):​c.*1615T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.811 in 154,036 control chromosomes in the GnomAD database, including 51,022 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 0.81 (50424 hom., cov: 33)
  • Exomes 𝑓: 0.80 (598 hom.)
• Consequence: CAST NM_001750.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640

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]

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.*1615T>G		3_prime_UTR_variant	32/32	ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.*1615T>G		3_prime_UTR_variant	32/32		NM_001750.7	A2

Frequencies

GnomAD3 genomes AF: 0.811 AC: 123350 AN: 152058 Hom.: 50372 Cov.: 33

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.856

Gnomad AMR AF: 0.854

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.806

GnomAD4 exome AF: 0.802 AC: 1491 AN: 1858 Hom.: 598 Cov.: 3 AF XY: 0.792 AC XY: 762 AN XY: 962

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.797

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.802

Gnomad4 NFE exome AF: 0.827

Gnomad4 OTH exome AF: 0.833

GnomAD4 genome AF: 0.811 AC: 123453 AN: 152178 Hom.: 50424 Cov.: 33 AF XY: 0.810 AC XY: 60291 AN XY: 74390

Gnomad4 AFR AF: 0.760

Gnomad4 AMR AF: 0.854

Gnomad4 ASJ AF: 0.829

Gnomad4 EAS AF: 0.590

Gnomad4 SAS AF: 0.795

Gnomad4 FIN AF: 0.803

Gnomad4 NFE AF: 0.851

Gnomad4 OTH AF: 0.807

Alfa AF: 0.843 Hom.: 52140

Bravo AF: 0.812

Asia WGS AF: 0.731 AC: 2544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs27433; hg19: chr5-96109935; COSMIC: COSV57087727; COSMIC: COSV57087727;