1-115698135-TC-TCC

Variant names:

• chr1-115698135-T-TC
• rs5777244
• NM_138959.3:c.*6763dupC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_138959.3(VANGL1):​c.*6763dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 152,030 control chromosomes in the GnomAD database, including 2,241 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2241 hom., cov: 30)
  • Failed GnomAD Quality Control
• Consequence: VANGL1 NM_138959.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.494
• Publications: 1 publications found

Genes affected

VANGL1 (HGNC:15512): (VANGL planar cell polarity protein 1) This gene encodes a member of the tretraspanin family. The encoded protein may be involved in mediating intestinal trefoil factor induced wound healing in the intestinal mucosa. Mutations in this gene are associated with neural tube defects. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

CASQ2 (HGNC:1513): (calsequestrin 2) The protein encoded by this gene specifies the cardiac muscle family member of the calsequestrin family. Calsequestrin is localized to the sarcoplasmic reticulum in cardiac and slow skeletal muscle cells. The protein is a calcium binding protein that stores calcium for muscle function. Mutations in this gene cause stress-induced polymorphic ventricular tachycardia, also referred to as catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2), a disease characterized by bidirectional ventricular tachycardia that may lead to cardiac arrest. [provided by RefSeq, Jul 2008]

CASQ2 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-115698135-T-TC is Benign according to our data. Variant chr1-115698135-T-TC is described in ClinVar as Likely_benign. ClinVar VariationId is 292113.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138959.3. 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
	VANGL1	NM_138959.3	MANE Select	c.*6763dupC		3_prime_UTR	Exon 8 of 8	NP_620409.1	Q8TAA9-1
	VANGL1	NM_001172412.2		c.*6763dupC		3_prime_UTR	Exon 8 of 8	NP_001165883.1	Q8TAA9-1
	VANGL1	NM_001172411.2		c.*6763dupC		3_prime_UTR	Exon 8 of 8	NP_001165882.1	Q8TAA9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VANGL1	ENST00000355485.7	TSL:1 MANE Select	c.*6763dupC		3_prime_UTR	Exon 8 of 8	ENSP00000347672.2	Q8TAA9-1
	VANGL1	ENST00000369510.8	TSL:1	c.*6763dupC		3_prime_UTR	Exon 8 of 8	ENSP00000358523.3	Q8TAA9-2
	CASQ2	ENST00000713711.1		c.*3105dupG		3_prime_UTR	Exon 12 of 12	ENSP00000519014.1	A0AAQ5BGS1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25125 AN: 151910 Hom.: 2230 Cov.: 30

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.169

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.165 AC: 25158 AN: 152030 Hom.: 2241 Cov.: 30 AF XY: 0.168 AC XY: 12456 AN XY: 74304

African (AFR) AF: 0.232 AC: 9635 AN: 41452

American (AMR) AF: 0.160 AC: 2450 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 603 AN: 3464

East Asian (EAS) AF: 0.132 AC: 684 AN: 5166

South Asian (SAS) AF: 0.126 AC: 609 AN: 4818

European-Finnish (FIN) AF: 0.184 AC: 1945 AN: 10566

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8768 AN: 67976

Other (OTH) AF: 0.167 AC: 353 AN: 2108

Alfa AF: 0.0540 Hom.: 45

Bravo AF: 0.166

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Caudal regression sequence (1)
-	-	1	Neural tube defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.49
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: rs5777244; hg19: chr1-116240756; COSMIC: COSV54769904; COSMIC: COSV54769904;