rs27689

Variant names:

• chr5-96771498-G-T
• rs27689
• NM_001750.7:c.2341-146G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-96771498-G-T
• chr5-96771498-G-A
• chr5-96771498-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001750.7(CAST):​c.2341-146G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 565,546 control chromosomes in the GnomAD database, including 232,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.91 (63845 hom., cov: 31)
  • Exomes 𝑓: 0.90 (168581 hom.)
• Consequence: CAST NM_001750.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.410
• Publications: 10 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]

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]

CAST (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 5-96771498-G-T is Benign according to our data. Variant chr5-96771498-G-T is described in ClinVar as Benign. ClinVar VariationId is 1220956.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.925 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.2341-146G>T		intron	N/A	NP_001741.4
	ERAP1	NM_001349244.2		c.2818+4906C>A		intron	N/A	NP_001336173.1	Q9NZ08-2
	ERAP1	NM_016442.5		c.2818+4906C>A		intron	N/A	NP_057526.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAST	ENST00000675179.1	MANE Select	c.2341-146G>T		intron	N/A	ENSP00000501872.1
	ERAP1	ENST00000296754.7	TSL:1	c.2818+4906C>A		intron	N/A	ENSP00000296754.3	Q9NZ08-2
	CAST	ENST00000341926.7	TSL:1	c.2092-146G>T		intron	N/A	ENSP00000339914.3

Frequencies

GnomAD3 genomes AF: 0.914 AC: 138888 AN: 152020 Hom.: 63785 Cov.: 31

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.918

Gnomad AMR AF: 0.938

Gnomad ASJ AF: 0.894

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.834

Gnomad FIN AF: 0.916

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.912

GnomAD4 exome AF: 0.900 AC: 372208 AN: 413408 Hom.: 168581 AF XY: 0.898 AC XY: 195854 AN XY: 218102

African (AFR) AF: 0.933 AC: 10023 AN: 10744

American (AMR) AF: 0.949 AC: 15114 AN: 15920

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 11428 AN: 12652

East Asian (EAS) AF: 0.715 AC: 20921 AN: 29274

South Asian (SAS) AF: 0.830 AC: 28118 AN: 33894

European-Finnish (FIN) AF: 0.915 AC: 32871 AN: 35928

Middle Eastern (MID) AF: 0.920 AC: 3153 AN: 3428

European-Non Finnish (NFE) AF: 0.925 AC: 228834 AN: 247378

Other (OTH) AF: 0.899 AC: 21746 AN: 24190

GnomAD4 genome AF: 0.914 AC: 139008 AN: 152138 Hom.: 63845 Cov.: 31 AF XY: 0.912 AC XY: 67826 AN XY: 74390

African (AFR) AF: 0.932 AC: 38713 AN: 41516

American (AMR) AF: 0.938 AC: 14340 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.894 AC: 3105 AN: 3472

East Asian (EAS) AF: 0.631 AC: 3255 AN: 5156

South Asian (SAS) AF: 0.834 AC: 4025 AN: 4826

European-Finnish (FIN) AF: 0.916 AC: 9704 AN: 10596

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.924 AC: 62834 AN: 67972

Other (OTH) AF: 0.911 AC: 1918 AN: 2106

Alfa AF: 0.922 Hom.: 36848

Bravo AF: 0.916

Asia WGS AF: 0.777 AC: 2705 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.6
DANN	Benign	0.50
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs27689; hg19: chr5-96107202;