5-96730948-C-T

Variant names:

• chr5-96730948-C-T
• rs151904
• NM_001750.7:c.630+88C>T

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.630+88C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 1,015,394 control chromosomes in the GnomAD database, including 261,641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35819 hom., cov: 32)
  • Exomes 𝑓: 0.72 (225822 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.293
• 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=-0.97).
• BP6: Variant 5-96730948-C-T is Benign according to our data. Variant chr5-96730948-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264261.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.630+88C>T		intron_variant	Intron 9 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.630+88C>T		intron_variant	Intron 9 of 31		NM_001750.7	ENSP00000501872.1
CAST	ENST00000508117.6	n.*154+88C>T		intron_variant	Intron 7 of 7	5		ENSP00000422466.1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103730 AN: 151890 Hom.: 35790 Cov.: 32

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.599

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.673

GnomAD4 exome AF: 0.722 AC: 623268 AN: 863386 Hom.: 225822 AF XY: 0.719 AC XY: 324093 AN XY: 450890

African (AFR) AF: 0.575 AC: 12707 AN: 22100

American (AMR) AF: 0.838 AC: 33925 AN: 40506

Ashkenazi Jewish (ASJ) AF: 0.605 AC: 13125 AN: 21680

East Asian (EAS) AF: 0.685 AC: 25213 AN: 36818

South Asian (SAS) AF: 0.642 AC: 46119 AN: 71886

European-Finnish (FIN) AF: 0.735 AC: 37665 AN: 51220

Middle Eastern (MID) AF: 0.596 AC: 2751 AN: 4612

European-Non Finnish (NFE) AF: 0.738 AC: 423543 AN: 573972

Other (OTH) AF: 0.695 AC: 28220 AN: 40592

GnomAD4 genome AF: 0.683 AC: 103803 AN: 152008 Hom.: 35819 Cov.: 32 AF XY: 0.684 AC XY: 50811 AN XY: 74302

African (AFR) AF: 0.577 AC: 23892 AN: 41424

American (AMR) AF: 0.770 AC: 11750 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.599 AC: 2079 AN: 3468

East Asian (EAS) AF: 0.643 AC: 3331 AN: 5178

South Asian (SAS) AF: 0.643 AC: 3102 AN: 4822

European-Finnish (FIN) AF: 0.732 AC: 7726 AN: 10556

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.731 AC: 49726 AN: 67982

Other (OTH) AF: 0.673 AC: 1421 AN: 2112

Alfa AF: 0.703 Hom.: 23947

Bravo AF: 0.683

Asia WGS AF: 0.665 AC: 2314 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	-0.97
CADD	Benign	2.7
DANN	Benign	0.57
PhyloP100		0.29
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: rs151904; hg19: chr5-96066652; COSMIC: COSV57785468; COSMIC: COSV57785468;