chr5-96734501-T-C

Variant names:

• chr5-96734501-T-C
• rs149313
• NM_001750.7:c.631-1671T>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.631-1671T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 152,040 control chromosomes in the GnomAD database, including 20,064 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 0.51 (20064 hom., cov: 32)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.377
• Publications: 15 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, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

CAST (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.631-1671T>C		intron	N/A	NP_001741.4
	CAST	NM_001042441.3		c.574-1671T>C		intron	N/A	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.565-1671T>C		intron	N/A	NP_001035907.1	P20810-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.631-1671T>C		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.382-1671T>C		intron	N/A	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.382-1671T>C		intron	N/A	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77954 AN: 151922 Hom.: 20048 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.483

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

GnomAD4 genome AF: 0.513 AC: 78014 AN: 152040 Hom.: 20064 Cov.: 32 AF XY: 0.512 AC XY: 38029 AN XY: 74298

African (AFR) AF: 0.485 AC: 20104 AN: 41440

American (AMR) AF: 0.489 AC: 7464 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1601 AN: 3470

East Asian (EAS) AF: 0.444 AC: 2302 AN: 5186

South Asian (SAS) AF: 0.511 AC: 2463 AN: 4824

European-Finnish (FIN) AF: 0.540 AC: 5695 AN: 10548

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36739 AN: 67976

Other (OTH) AF: 0.484 AC: 1025 AN: 2116

Alfa AF: 0.528 Hom.: 89589

Bravo AF: 0.508

Asia WGS AF: 0.508 AC: 1769 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.6
DANN	Benign	0.65
PhyloP100		0.38
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: rs149313; hg19: chr5-96070205;