5-96520975-A-G

Variant names:

• chr5-96520975-A-G
• rs2570467
• NM_001423250.1:c.-175+141323A>G

Variant summary

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

The NM_001423250.1(CAST):​c.-175+141323A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,054 control chromosomes in the GnomAD database, including 7,173 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 0.29 (7173 hom., cov: 31)
• Consequence: CAST NM_001423250.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAST	NM_001423250.1	c.-175+141323A>G		intron_variant	Intron 5 of 35		NP_001410179.1
CAST	NM_001423251.1	c.-175+141323A>G		intron_variant	Intron 5 of 34		NP_001410180.1
CAST	NM_001423252.1	c.-175+141323A>G		intron_variant	Intron 4 of 33		NP_001410181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAST	ENST00000718093.1	c.-175+141323A>G		intron_variant	Intron 3 of 30			ENSP00000520668.1
CAST	ENST00000718091.1	c.-175+141323A>G		intron_variant	Intron 3 of 11			ENSP00000520667.1
CAST	ENST00000718090.1	n.241-109992A>G		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43732 AN: 151936 Hom.: 7172 Cov.: 31

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.290

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

GnomAD4 genome AF: 0.288 AC: 43753 AN: 152054 Hom.: 7173 Cov.: 31 AF XY: 0.289 AC XY: 21479 AN XY: 74314

African (AFR) AF: 0.133 AC: 5520 AN: 41488

American (AMR) AF: 0.268 AC: 4094 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1178 AN: 3470

East Asian (EAS) AF: 0.138 AC: 714 AN: 5174

South Asian (SAS) AF: 0.310 AC: 1490 AN: 4804

European-Finnish (FIN) AF: 0.395 AC: 4172 AN: 10570

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.376 AC: 25533 AN: 67950

Other (OTH) AF: 0.291 AC: 615 AN: 2110

Alfa AF: 0.320 Hom.: 2917

Bravo AF: 0.271

Asia WGS AF: 0.219 AC: 760 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.0
DANN	Benign	0.75
PhyloP100		-0.10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2570467; hg19: chr5-95856679;