NM_001750.7:c.138+2136G>C

Variant names:

• chr5-96677737-G-C
• rs31250
• NM_001750.7:c.138+2136G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001750.7(CAST):​c.138+2136G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,130 control chromosomes in the GnomAD database, including 8,590 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 0.30 (8590 hom., cov: 32)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.138+2136G>C		intron_variant	Intron 2 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.138+2136G>C		intron_variant	Intron 2 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46066 AN: 152012 Hom.: 8570 Cov.: 32

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.292

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.303 AC: 46126 AN: 152130 Hom.: 8590 Cov.: 32 AF XY: 0.301 AC XY: 22383 AN XY: 74384

African (AFR) AF: 0.522 AC: 21669 AN: 41476

American (AMR) AF: 0.214 AC: 3265 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 926 AN: 3468

East Asian (EAS) AF: 0.320 AC: 1657 AN: 5182

South Asian (SAS) AF: 0.280 AC: 1349 AN: 4822

European-Finnish (FIN) AF: 0.181 AC: 1912 AN: 10576

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14356 AN: 68008

Other (OTH) AF: 0.294 AC: 621 AN: 2114

Alfa AF: 0.110 Hom.: 165

Bravo AF: 0.314

Asia WGS AF: 0.292 AC: 1017 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	4.2
DANN	Benign	0.68
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs31250; hg19: chr5-96013441; COSMIC: COSV57783617; COSMIC: COSV57783617;