chr5-96749244-T-G

Variant names:

• chr5-96749244-T-G
• rs3756623
• NM_001750.7:c.1428+631T>G

Variant summary

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

The NM_001750.7(CAST):​c.1428+631T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0965 in 152,220 control chromosomes in the GnomAD database, including 854 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 0.096 (854 hom., cov: 32)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750
• Publications: 7 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	NM_001750.7	MANE Select	c.1428+631T>G		intron	N/A	NP_001741.4
	CAST	NM_001042441.3		c.1371+631T>G		intron	N/A	NP_001035906.1
	CAST	NM_001042442.3		c.1362+631T>G		intron	N/A	NP_001035907.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.1428+631T>G		intron	N/A	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1179+631T>G		intron	N/A	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.1140+631T>G		intron	N/A	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.0964 AC: 14669 AN: 152102 Hom.: 855 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.0725

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0267

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0403

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0735

Gnomad OTH AF: 0.102

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

GnomAD4 genome AF: 0.0965 AC: 14682 AN: 152220 Hom.: 854 Cov.: 32 AF XY: 0.0965 AC XY: 7180 AN XY: 74440

African (AFR) AF: 0.153 AC: 6360 AN: 41526

American (AMR) AF: 0.0724 AC: 1106 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3468

East Asian (EAS) AF: 0.0268 AC: 139 AN: 5186

South Asian (SAS) AF: 0.135 AC: 651 AN: 4822

European-Finnish (FIN) AF: 0.0403 AC: 427 AN: 10608

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0735 AC: 4999 AN: 68010

Other (OTH) AF: 0.103 AC: 217 AN: 2110

Alfa AF: 0.0851 Hom.: 341

Bravo AF: 0.100

Asia WGS AF: 0.0900 AC: 313 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.5
DANN	Benign	0.82
PhyloP100		-0.075
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: rs3756623; hg19: chr5-96084948;