5-96774231-T-G

Variant names:

• chr5-96774231-T-G
• rs27433
• NM_001750.7:c.*1615T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 28 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: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.*1615T>G		3_prime_UTR	Exon 32 of 32	NP_001741.4
	CAST	NM_001042441.3		c.*1615T>G		3_prime_UTR	Exon 31 of 31	NP_001035906.1
	CAST	NM_001042442.3		c.*1615T>G		3_prime_UTR	Exon 31 of 31	NP_001035907.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.*1615T>G		3_prime_UTR	Exon 32 of 32	ENSP00000501872.1
	CAST	ENST00000309190.9	TSL:1	c.*1615T>G		3_prime_UTR	Exon 29 of 29	ENSP00000312523.5
	CAST	ENST00000437034.6	TSL:1	c.*1615T>G		3_prime_UTR	Exon 18 of 18	ENSP00000412374.2

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

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.797 AC: 110 AN: 138

South Asian (SAS) AF: 0.250 AC: 1 AN: 4

European-Finnish (FIN) AF: 0.802 AC: 1232 AN: 1536

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.827 AC: 129 AN: 156

Other (OTH) AF: 0.833 AC: 15 AN: 18

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

African (AFR) AF: 0.760 AC: 31535 AN: 41520

American (AMR) AF: 0.854 AC: 13055 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 2877 AN: 3470

East Asian (EAS) AF: 0.590 AC: 3056 AN: 5180

South Asian (SAS) AF: 0.795 AC: 3833 AN: 4820

European-Finnish (FIN) AF: 0.803 AC: 8475 AN: 10560

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.851 AC: 57899 AN: 68020

Other (OTH) AF: 0.807 AC: 1703 AN: 2110

Alfa AF: 0.840 Hom.: 67719

Bravo AF: 0.812

Asia WGS AF: 0.731 AC: 2544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.67
PhyloP100		-0.064
Mutation Taster		=100/0	polymorphism (auto)

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