NM_001750.7:c.168A>G

Variant names:

• chr5-96695865-A-G
• rs9667
• NM_001750.7:c.168A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001750.7(CAST):​c.168A>G​(p.Gln56Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,608,786 control chromosomes in the GnomAD database, including 34,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2742 hom., cov: 31)
  • Exomes 𝑓: 0.20 (31447 hom.)
• Consequence: CAST NM_001750.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.01
• Publications: 22 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.022).
• BP6: Variant 5-96695865-A-G is Benign according to our data. Variant chr5-96695865-A-G is described in ClinVar as Benign. ClinVar VariationId is 1192696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 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.168A>G	p.Gln56Gln	synonymous	Exon 3 of 32	NP_001741.4
	CAST	NM_001042441.3		c.168A>G	p.Gln56Gln	synonymous	Exon 3 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.168A>G	p.Gln56Gln	synonymous	Exon 3 of 31	NP_001035907.1	P20810-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.168A>G	p.Gln56Gln	synonymous	Exon 3 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.-82A>G		5_prime_UTR	Exon 1 of 30	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.-82A>G		5_prime_UTR	Exon 3 of 31	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28353 AN: 151990 Hom.: 2739 Cov.: 31

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.211 AC: 52378 AN: 247922 AF XY: 0.212

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.205 AC: 298314 AN: 1456678 Hom.: 31447 Cov.: 30 AF XY: 0.206 AC XY: 149102 AN XY: 724680

African (AFR) AF: 0.123 AC: 4107 AN: 33386

American (AMR) AF: 0.232 AC: 10289 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 3512 AN: 26050

East Asian (EAS) AF: 0.261 AC: 10331 AN: 39572

South Asian (SAS) AF: 0.221 AC: 18965 AN: 85772

European-Finnish (FIN) AF: 0.254 AC: 13543 AN: 53224

Middle Eastern (MID) AF: 0.153 AC: 878 AN: 5748

European-Non Finnish (NFE) AF: 0.203 AC: 224871 AN: 1108312

Other (OTH) AF: 0.196 AC: 11818 AN: 60204

GnomAD4 genome AF: 0.186 AC: 28360 AN: 152108 Hom.: 2742 Cov.: 31 AF XY: 0.190 AC XY: 14144 AN XY: 74350

African (AFR) AF: 0.132 AC: 5458 AN: 41490

American (AMR) AF: 0.210 AC: 3204 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3466

East Asian (EAS) AF: 0.234 AC: 1211 AN: 5182

South Asian (SAS) AF: 0.226 AC: 1090 AN: 4820

European-Finnish (FIN) AF: 0.257 AC: 2713 AN: 10562

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13731 AN: 67980

Other (OTH) AF: 0.173 AC: 366 AN: 2112

Alfa AF: 0.198 Hom.: 12920

Bravo AF: 0.179

Asia WGS AF: 0.259 AC: 901 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.193

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.59
PhyloP100		-1.0
PromoterAI		0.0023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs9667; hg19: chr5-96031569; COSMIC: COSV57782905; COSMIC: COSV57782905;