5-96757518-G-A

Variant names:

• chr5-96757518-G-A
• rs27654
• NM_001750.7:c.1761+24G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001750.7(CAST):​c.1761+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,611,976 control chromosomes in the GnomAD database, including 96,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (10341 hom., cov: 31)
  • Exomes 𝑓: 0.34 (86197 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.278
• Publications: 17 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 Gene-Disease associations (from GenCC):

• peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-96757518-G-A is Benign according to our data. Variant chr5-96757518-G-A is described in ClinVar as [Benign]. Clinvar id is 1239061.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1761+24G>A		intron_variant	Intron 23 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1761+24G>A		intron_variant	Intron 23 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54834 AN: 151788 Hom.: 10316 Cov.: 31

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.342

GnomAD2 exomes AF: 0.378 AC: 94958 AN: 251262 AF XY: 0.368

Gnomad AFR exome AF: 0.399

Gnomad AMR exome AF: 0.561

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.337 AC: 491527 AN: 1460070 Hom.: 86197 Cov.: 34 AF XY: 0.336 AC XY: 244286 AN XY: 726478

African (AFR) AF: 0.400 AC: 13375 AN: 33442

American (AMR) AF: 0.551 AC: 24650 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 7546 AN: 26114

East Asian (EAS) AF: 0.563 AC: 22325 AN: 39664

South Asian (SAS) AF: 0.347 AC: 29915 AN: 86226

European-Finnish (FIN) AF: 0.370 AC: 19769 AN: 53416

Middle Eastern (MID) AF: 0.289 AC: 1665 AN: 5760

European-Non Finnish (NFE) AF: 0.317 AC: 352012 AN: 1110400

Other (OTH) AF: 0.336 AC: 20270 AN: 60328

GnomAD4 genome AF: 0.361 AC: 54906 AN: 151906 Hom.: 10341 Cov.: 31 AF XY: 0.366 AC XY: 27163 AN XY: 74234

African (AFR) AF: 0.397 AC: 16418 AN: 41406

American (AMR) AF: 0.450 AC: 6864 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1025 AN: 3460

East Asian (EAS) AF: 0.512 AC: 2641 AN: 5160

South Asian (SAS) AF: 0.354 AC: 1707 AN: 4820

European-Finnish (FIN) AF: 0.359 AC: 3784 AN: 10548

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21458 AN: 67942

Other (OTH) AF: 0.344 AC: 725 AN: 2110

Alfa AF: 0.334 Hom.: 25448

Bravo AF: 0.369

Asia WGS AF: 0.451 AC: 1568 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.4
DANN	Benign	0.57
PhyloP100		0.28
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: rs27654; hg19: chr5-96093222; COSMIC: COSV57087718; COSMIC: COSV57087718;