rs7733671

Variant names:

• chr5-96664565-G-A
• rs7733671
• NM_001750.7:c.75+2068G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-96664565-G-A
• chr5-96664565-G-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.75+2068G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 151,974 control chromosomes in the GnomAD database, including 11,224 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 0.34 (11224 hom., cov: 31)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 10 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001750.7	c.75+2068G>A		intron_variant	Intron 1 of 31	ENST00000675179.1	NP_001741.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000675179.1	c.75+2068G>A		intron_variant	Intron 1 of 31		NM_001750.7	ENSP00000501872.1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51210 AN: 151858 Hom.: 11192 Cov.: 31

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.316

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

GnomAD4 genome AF: 0.337 AC: 51291 AN: 151974 Hom.: 11224 Cov.: 31 AF XY: 0.335 AC XY: 24897 AN XY: 74302

African (AFR) AF: 0.620 AC: 25695 AN: 41442

American (AMR) AF: 0.248 AC: 3786 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 925 AN: 3466

East Asian (EAS) AF: 0.333 AC: 1719 AN: 5162

South Asian (SAS) AF: 0.314 AC: 1512 AN: 4816

European-Finnish (FIN) AF: 0.181 AC: 1916 AN: 10566

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14693 AN: 67932

Other (OTH) AF: 0.317 AC: 669 AN: 2110

Alfa AF: 0.252 Hom.: 3212

Bravo AF: 0.354

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.13
DANN	Benign	0.13
PhyloP100		-1.4
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: rs7733671; hg19: chr5-96000269; COSMIC: COSV57783514;