rs27852

Variant names:

• chr5-96710335-A-C
• rs27852
• NM_001750.7:c.211-12304A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-96710335-A-C
• chr5-96710335-A-G
• chr5-96710335-A-T

Variant summary

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

The NM_001750.7(CAST):​c.211-12304A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 151,906 control chromosomes in the GnomAD database, including 31,726 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 0.64 (31726 hom., cov: 31)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.75
• Publications: 16 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=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.211-12304A>C		intron_variant	Intron 3 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.211-12304A>C		intron_variant	Intron 3 of 31		NM_001750.7	ENSP00000501872.1
CAST	ENST00000508117.6	n.-40+7420A>C		intron_variant	Intron 1 of 7	5		ENSP00000422466.1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97425 AN: 151788 Hom.: 31699 Cov.: 31

Gnomad AFR AF: 0.564

Gnomad AMI AF: 0.633

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.692

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.658

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

GnomAD4 genome AF: 0.642 AC: 97494 AN: 151906 Hom.: 31726 Cov.: 31 AF XY: 0.639 AC XY: 47458 AN XY: 74216

African (AFR) AF: 0.564 AC: 23369 AN: 41400

American (AMR) AF: 0.610 AC: 9320 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2313 AN: 3472

East Asian (EAS) AF: 0.456 AC: 2349 AN: 5154

South Asian (SAS) AF: 0.597 AC: 2874 AN: 4814

European-Finnish (FIN) AF: 0.681 AC: 7178 AN: 10546

Middle Eastern (MID) AF: 0.697 AC: 202 AN: 290

European-Non Finnish (NFE) AF: 0.705 AC: 47924 AN: 67936

Other (OTH) AF: 0.658 AC: 1389 AN: 2110

Alfa AF: 0.682 Hom.: 57917

Bravo AF: 0.636

Asia WGS AF: 0.560 AC: 1950 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.21
DANN	Benign	0.38
PhyloP100		-1.8
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: rs27852; hg19: chr5-96046039; COSMIC: COSV107351393;