15-34788730-T-C

Variant names:

• chr15-34788730-T-C
• rs533021
• ENST00000503496.6:n.299+11299T>C

Variant summary

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

The ENST00000503496.6(GJD2-DT):​n.299+11299T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 152,060 control chromosomes in the GnomAD database, including 24,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24431 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GJD2-DT ENST00000503496.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.167
• Publications: 18 publications found

Genes affected

GJD2-DT (HGNC:55560): (GJD2 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-34788730-T-C is Benign according to our data. Variant chr15-34788730-T-C is described in ClinVar as Benign. ClinVar VariationId is 315653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000503496.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJD2-DT	NR_120329.1		n.299+11299T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJD2-DT	ENST00000503496.6	TSL:2	n.299+11299T>C		intron	N/A
	GJD2-DT	ENST00000558707.4	TSL:3	n.322-1077T>C		intron	N/A
	GJD2-DT	ENST00000671663.2		n.139-21766T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83756 AN: 151942 Hom.: 24430 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.744

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.693

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.566

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: 0.551 AC: 83785 AN: 152060 Hom.: 24431 Cov.: 32 AF XY: 0.551 AC XY: 40919 AN XY: 74318

African (AFR) AF: 0.374 AC: 15494 AN: 41454

American (AMR) AF: 0.498 AC: 7603 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2375 AN: 3466

East Asian (EAS) AF: 0.371 AC: 1917 AN: 5172

South Asian (SAS) AF: 0.533 AC: 2567 AN: 4818

European-Finnish (FIN) AF: 0.693 AC: 7327 AN: 10578

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.654 AC: 44454 AN: 67978

Other (OTH) AF: 0.564 AC: 1192 AN: 2112

Alfa AF: 0.609 Hom.: 68622

Bravo AF: 0.527

Asia WGS AF: 0.437 AC: 1523 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1R Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Hypertrophic cardiomyopathy 11 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.7
DANN	Benign	0.68
PhyloP100		0.17
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: rs533021; hg19: chr15-35080931;