5-96762275-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.72

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]

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

Verdict is Benign. Variant got -20 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 id is 709742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAST	NM_001750.7	c.1835A>G	p.Lys612Arg	missense_variant, splice_region_variant	25/32	ENST00000675179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAST	ENST00000675179.1	c.1835A>G	p.Lys612Arg	missense_variant, splice_region_variant	25/32		NM_001750.7	A2

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

GnomAD3 exomes AF: 0.00187 AC: 448 AN: 239302 Hom.: 4 AF XY: 0.00151 AC XY: 196 AN XY: 129716

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 SAS exome AF: 0.00230

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

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.00179

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

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00163 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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

CAST-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 28, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0045	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	N;N;N;N;N;N;.;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.020
Sift	Benign	0.13	T;T;T;T;T;T;.;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.20	B;B;.;.;.;B;B;B;.;.;B;.;B;.;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

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.20
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

Publications

LitVar

Other links and lift over

dbSNP: rs61744247; hg19: chr5-96097979;