15-34788359-C-A

Variant names:

• chr15-34788359-C-A
• rs79955486
• ENST00000503496.6:n.299+10928C>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000503496.6(GJD2-DT):​n.299+10928C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 152,220 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0069 (17 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: GJD2-DT ENST00000503496.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.386

Genes affected

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

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-34788359-C-A is Benign according to our data. Variant chr15-34788359-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 888010.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0069 (1050/152220) while in subpopulation AFR AF= 0.024 (998/41528). AF 95% confidence interval is 0.0228. There are 17 homozygotes in gnomad4. There are 485 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD2-DT	NR_120329.1	n.299+10928C>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJD2-DT	ENST00000503496.6	n.299+10928C>A		intron_variant	Intron 2 of 2	2
GJD2-DT	ENST00000558707.3	n.280-1448C>A		intron_variant	Intron 2 of 2	3
GJD2-DT	ENST00000671663.1	n.95-22137C>A		intron_variant	Intron 1 of 1
GJD2-DT	ENST00000693120.2	n.117-1448C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00688 AC: 1046 AN: 152102 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

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

GnomAD4 genome AF: 0.00690 AC: 1050 AN: 152220 Hom.: 17 Cov.: 31 AF XY: 0.00652 AC XY: 485 AN XY: 74418

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00158 Hom.: 0

Bravo AF: 0.00756

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1R Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hypertrophic cardiomyopathy 11 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.4
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs79955486; hg19: chr15-35080560;