rs61744247

Variant names:

• chr5-96762275-A-G
• rs61744247
• NM_001750.7:c.1835A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001750.7(CAST):​c.1835A>G​(p.Lys612Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,600,692 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0060 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (14 hom.)
• Consequence: CAST NM_001750.7 missense, splice_region
• Scores: Splicing: ADA: 0.001810
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.72
• 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 (HGNC:):

ERAP1 (HGNC:18173): (endoplasmic reticulum aminopeptidase 1) The protein encoded by this gene is an aminopeptidase involved in trimming HLA class I-binding precursors so that they can be presented on MHC class I molecules. The encoded protein acts as a monomer or as a heterodimer with ERAP2. This protein may also be involved in blood pressure regulation by inactivation of angiotensin II. Three transcript variants encoding two different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004529983).
• BP6: Variant 5-96762275-A-G is Benign according to our data. Variant chr5-96762275-A-G is described in ClinVar as Benign. ClinVar VariationId is 709742.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00601 (915/152266) while in subpopulation AFR AF = 0.02 (830/41554). AF 95% confidence interval is 0.0188. There are 10 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.1835A>G	p.Lys612Arg	missense splice_region	Exon 25 of 32	NP_001741.4
	CAST	NM_001042441.3		c.1778A>G	p.Lys593Arg	missense splice_region	Exon 24 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.1769A>G	p.Lys590Arg	missense splice_region	Exon 24 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.1835A>G	p.Lys612Arg	missense splice_region	Exon 25 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1586A>G	p.Lys529Arg	missense splice_region	Exon 23 of 30	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.1547A>G	p.Lys516Arg	missense splice_region	Exon 24 of 31	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 913 AN: 152148 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00187 AC: 448 AN: 239302 AF XY: 0.00151

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000910

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000286

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000849 AC: 1229 AN: 1448426 Hom.: 14 Cov.: 30 AF XY: 0.000851 AC XY: 613 AN XY: 720680

African (AFR) AF: 0.0214 AC: 697 AN: 32616

American (AMR) AF: 0.00122 AC: 50 AN: 40818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25642

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39424

South Asian (SAS) AF: 0.00242 AC: 202 AN: 83404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53196

Middle Eastern (MID) AF: 0.00455 AC: 26 AN: 5716

European-Non Finnish (NFE) AF: 0.000128 AC: 142 AN: 1107890

Other (OTH) AF: 0.00179 AC: 107 AN: 59720

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152266 Hom.: 10 Cov.: 32 AF XY: 0.00576 AC XY: 429 AN XY: 74440

African (AFR) AF: 0.0200 AC: 830 AN: 41554

American (AMR) AF: 0.00294 AC: 45 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00202 Hom.: 3

Bravo AF: 0.00670

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00208 AC: 253

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CAST-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.020
Sift	Benign	0.13	T
Sift4G	Benign	0.26	T
Polyphen		0.20	B
Vest4		0.096
MVP		0.49
MPC		0.068
ClinPred		0.020	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.037
gMVP		0.052
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.20
Splicevardb		1.0
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 1

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

Other links and lift over

dbSNP: rs61744247; hg19: chr5-96097979;