5-96754272-A-G

Variant names:

• chr5-96754272-A-G
• rs27772
• NM_001750.7:c.1626+111A>G

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.1626+111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 736,358 control chromosomes in the GnomAD database, including 50,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11050 hom., cov: 33)
  • Exomes 𝑓: 0.36 (39590 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.761
• 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=-0.88).
• BP6: Variant 5-96754272-A-G is Benign according to our data. Variant chr5-96754272-A-G is described in ClinVar as Benign. ClinVar VariationId is 1182630.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.1626+111A>G		intron_variant	Intron 21 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1626+111A>G		intron_variant	Intron 21 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56585 AN: 152078 Hom.: 11020 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.350

GnomAD4 exome AF: 0.355 AC: 207607 AN: 584160 Hom.: 39590 AF XY: 0.353 AC XY: 110377 AN XY: 312358

African (AFR) AF: 0.439 AC: 6892 AN: 15696

American (AMR) AF: 0.539 AC: 17124 AN: 31786

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 5218 AN: 18242

East Asian (EAS) AF: 0.579 AC: 18712 AN: 32306

South Asian (SAS) AF: 0.351 AC: 20533 AN: 58514

European-Finnish (FIN) AF: 0.371 AC: 17072 AN: 45994

Middle Eastern (MID) AF: 0.278 AC: 911 AN: 3274

European-Non Finnish (NFE) AF: 0.318 AC: 110553 AN: 347398

Other (OTH) AF: 0.342 AC: 10592 AN: 30950

GnomAD4 genome AF: 0.372 AC: 56661 AN: 152198 Hom.: 11050 Cov.: 33 AF XY: 0.376 AC XY: 28012 AN XY: 74404

African (AFR) AF: 0.434 AC: 17997 AN: 41514

American (AMR) AF: 0.453 AC: 6929 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1014 AN: 3472

East Asian (EAS) AF: 0.513 AC: 2657 AN: 5184

South Asian (SAS) AF: 0.357 AC: 1724 AN: 4826

European-Finnish (FIN) AF: 0.359 AC: 3801 AN: 10594

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21512 AN: 67992

Other (OTH) AF: 0.351 AC: 742 AN: 2114

Alfa AF: 0.340 Hom.: 7005

Bravo AF: 0.381

Asia WGS AF: 0.454 AC: 1581 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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.45
DANN	Benign	0.51
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs27772; hg19: chr5-96089976; COSMIC: COSV57786483; COSMIC: COSV57786483;