5-96765303-A-C

Variant names:

• chr5-96765303-A-C
• rs541132407
• NM_001750.7:c.2015A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001750.7(CAST):​c.2015A>C​(p.Lys672Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000651 in 1,535,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: CAST NM_001750.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13
• Publications: 3 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2015A>C	p.Lys672Thr	missense	Exon 26 of 32	NP_001741.4
	CAST	NM_001042441.3		c.1958A>C	p.Lys653Thr	missense	Exon 25 of 31	NP_001035906.1	P20810-7
	CAST	NM_001042442.3		c.1949A>C	p.Lys650Thr	missense	Exon 25 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.2015A>C	p.Lys672Thr	missense	Exon 26 of 32	ENSP00000501872.1
	CAST	ENST00000341926.7	TSL:1	c.1766A>C	p.Lys589Thr	missense	Exon 24 of 30	ENSP00000339914.3
	CAST	ENST00000338252.7	TSL:1	c.1727A>C	p.Lys576Thr	missense	Exon 25 of 31	ENSP00000343421.3

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150408 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000578 AC: 8 AN: 1384580 Hom.: 0 Cov.: 24 AF XY: 0.00000578 AC XY: 4 AN XY: 692166

African (AFR) AF: 0.0000644 AC: 2 AN: 31072

American (AMR) AF: 0.00 AC: 0 AN: 41030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25152

East Asian (EAS) AF: 0.00 AC: 0 AN: 39266

South Asian (SAS) AF: 0.00 AC: 0 AN: 80858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050934

Other (OTH) AF: 0.000104 AC: 6 AN: 57614

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150522 Hom.: 0 Cov.: 28 AF XY: 0.0000136 AC XY: 1 AN XY: 73450

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000489 AC: 2 AN: 40882

American (AMR) AF: 0.00 AC: 0 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67688

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.040	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.38
Sift	Benign	0.030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.44		Loss of methylation at K650 (P = 0.0032)
MVP		0.40
MPC		0.26
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.13
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs541132407; hg19: chr5-96101007;