5-96742633-C-G

Variant names:

• chr5-96742633-C-G
• rs10515244
• NM_001750.7:c.1099-22C>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.1099-22C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,505,340 control chromosomes in the GnomAD database, including 11,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.094 (883 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10656 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.374
• Publications: 11 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=-0.66).
• BP6: Variant 5-96742633-C-G is Benign according to our data. Variant chr5-96742633-C-G is described in ClinVar as Benign. ClinVar VariationId is 1221320.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.1099-22C>G		intron_variant	Intron 15 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.1099-22C>G		intron_variant	Intron 15 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 14319 AN: 152026 Hom.: 882 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.0780

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.102 AC: 25358 AN: 248328 AF XY: 0.105

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.0697

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.00132

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.120 AC: 162912 AN: 1353194 Hom.: 10656 Cov.: 21 AF XY: 0.120 AC XY: 81475 AN XY: 679548

African (AFR) AF: 0.0209 AC: 657 AN: 31446

American (AMR) AF: 0.0738 AC: 3273 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2904 AN: 25426

East Asian (EAS) AF: 0.000741 AC: 29 AN: 39140

South Asian (SAS) AF: 0.0756 AC: 6338 AN: 83834

European-Finnish (FIN) AF: 0.129 AC: 6874 AN: 53250

Middle Eastern (MID) AF: 0.103 AC: 572 AN: 5566

European-Non Finnish (NFE) AF: 0.134 AC: 136015 AN: 1013426

Other (OTH) AF: 0.110 AC: 6250 AN: 56762

GnomAD4 genome AF: 0.0941 AC: 14319 AN: 152146 Hom.: 883 Cov.: 32 AF XY: 0.0941 AC XY: 6999 AN XY: 74360

African (AFR) AF: 0.0229 AC: 950 AN: 41524

American (AMR) AF: 0.101 AC: 1540 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.0785 AC: 378 AN: 4816

European-Finnish (FIN) AF: 0.133 AC: 1403 AN: 10570

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9257 AN: 67994

Other (OTH) AF: 0.122 AC: 257 AN: 2110

Alfa AF: 0.113 Hom.: 185

Bravo AF: 0.0888

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

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	-0.66
CADD	Benign	2.0
DANN	Benign	0.80
PhyloP100		-0.37
PromoterAI		-0.010	Neutral
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: rs10515244; hg19: chr5-96078337; COSMIC: COSV57784020; COSMIC: COSV57784020;