NM_004004.6:c.-23+12G>A
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting
The NM_004004.6(GJB2):c.-23+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 152,182 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_004004.6 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00542 AC: 824AN: 152076Hom.: 10 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 792Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 468
GnomAD4 genome AF: 0.00543 AC: 827AN: 152182Hom.: 10 Cov.: 33 AF XY: 0.00555 AC XY: 413AN XY: 74406
ClinVar
Submissions by phenotype
not specified Benign:3
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Variant summary: The GJB2 c.-23+12G>A variant involves the alteration of a non-conserved nucleotide in the first intron of the gene. One in silico tool predicts a benign outcome for this variant and 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 167/30820 control chromosomes (2 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.018983 (165/8692). This frequency is about 56 times the estimated maximal expected allele frequency of a dominant pathogenic GJB2 variant (0.0003376), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In a recessive inheritance model, this frequency does not exceed the maximal expected frequency for a recessive pathogenic GJB2 variant (0.02598). However, the presence of two normal homozygous individuals in the gnomAD database support a benign impact of this variant in either inheritance model. The variant has been found in at least 7 hearing loss patients. However, in 6 reported patients, this variant was found in heterozygous state, suggesting that this variant might not explain the phenotype in the patients because hearing loss is predominantly a recessive disorder, and the high allele frequency in African controls suggests that this variant is not a dominant hearing loss causative variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign or benign. Taken together, this variant is classified as benign. -
c.-23+12G>A in intron 1 of GJB2: This variant is not expected to have clinical s ignificance because it has been identified in 1.9% (165/8692) of African chromos omes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs397516866). -
not provided Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at