NM_138959.3:c.*6721A>G

Variant names:

• chr1-115698100-A-G
• rs17034249
• NM_138959.3:c.*6721A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138959.3(VANGL1):​c.*6721A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 152,174 control chromosomes in the GnomAD database, including 992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (992 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: VANGL1 NM_138959.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-115698100-A-G is Benign according to our data. Variant chr1-115698100-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 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.*6721A>G		3_prime_UTR	Exon 8 of 8	NP_620409.1	Q8TAA9-1
	VANGL1	NM_001172412.2		c.*6721A>G		3_prime_UTR	Exon 8 of 8	NP_001165883.1	Q8TAA9-1
	VANGL1	NM_001172411.2		c.*6721A>G		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.*6721A>G		3_prime_UTR	Exon 8 of 8	ENSP00000347672.2	Q8TAA9-1
	VANGL1	ENST00000369510.8	TSL:1	c.*6721A>G		3_prime_UTR	Exon 8 of 8	ENSP00000358523.3	Q8TAA9-2
	CASQ2	ENST00000713711.1		c.*3141T>C		3_prime_UTR	Exon 12 of 12	ENSP00000519014.1	A0AAQ5BGS1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15630 AN: 152056 Hom.: 990 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0595

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0944

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.101

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: 0.103 AC: 15643 AN: 152174 Hom.: 992 Cov.: 33 AF XY: 0.102 AC XY: 7596 AN XY: 74408

African (AFR) AF: 0.175 AC: 7238 AN: 41476

American (AMR) AF: 0.0595 AC: 910 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3468

East Asian (EAS) AF: 0.0998 AC: 517 AN: 5180

South Asian (SAS) AF: 0.0392 AC: 189 AN: 4826

European-Finnish (FIN) AF: 0.0944 AC: 1000 AN: 10596

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0754 AC: 5128 AN: 68018

Other (OTH) AF: 0.0994 AC: 210 AN: 2112

Alfa AF: 0.0826 Hom.: 401

Bravo AF: 0.102

Asia WGS AF: 0.0730 AC: 255 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	-	1	Neural tube defect (1)
-	-	1	not provided (1)
-	-	1	Sacral defect with anterior meningocele (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.8
DANN	Benign	0.85
PhyloP100		1.4
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: rs17034249; hg19: chr1-116240721;