15-34788680-C-G

Position:

• chr15-34788680-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NR_120329.1(GJD2-DT):​n.299+11249C>G variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000973 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GJD2-DT NR_120329.1 intron, non_coding_transcript
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.407

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-34788680-C-G is Benign according to our data. Variant chr15-34788680-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 885807.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJD2-DT	NR_120329.1	n.299+11249C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJD2-DT	ENST00000671663.1	n.95-21816C>G		intron_variant, non_coding_transcript_variant
GJD2-DT	ENST00000503496.6	n.299+11249C>G		intron_variant, non_coding_transcript_variant		2
GJD2-DT	ENST00000558707.3	n.280-1127C>G		intron_variant, non_coding_transcript_variant		3
GJD2-DT	ENST00000693120.2	n.117-1127C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 148 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00287

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

GnomAD4 genome AF: 0.000973 AC: 148 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.000888 AC XY: 66 AN XY: 74332

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.0000694 Hom.: 0

Bravo AF: 0.00104

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1R Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hypertrophic cardiomyopathy 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

ACTC1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.87
DANN	Benign	0.65

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: rs750495564; hg19: chr15-35080881;