chr1-34785412-GCCTGCACAAGGA-G

Variant names:

• chr1-34785412-GCCTGCACAAGGA-G
• rs727503069
• NM_024009.3:c.652_663delCTGCACAAGGAC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4 BP6 BS1

The NM_024009.3(GJB3):​c.652_663delCTGCACAAGGAC​(p.Leu218_Asp221del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,614,024 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: GJB3 NM_024009.3 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 1.89
• Publications: 1 publications found

Genes affected

GJB3 (HGNC:4285): (gap junction protein beta 3) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255811 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_024009.3.
• BP6: Variant 1-34785412-GCCTGCACAAGGA-G is Benign according to our data. Variant chr1-34785412-GCCTGCACAAGGA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163536.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000236 (345/1461862) while in subpopulation MID AF = 0.00486 (28/5764). AF 95% confidence interval is 0.00345. There are 1 homozygotes in GnomAdExome4. There are 172 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024009.3. 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
	GJB3	NM_024009.3	MANE Select	c.652_663delCTGCACAAGGAC	p.Leu218_Asp221del	conservative_inframe_deletion	Exon 2 of 2	NP_076872.1	O75712
	GJB3	NM_001005752.2		c.652_663delCTGCACAAGGAC	p.Leu218_Asp221del	conservative_inframe_deletion	Exon 2 of 2	NP_001005752.1	O75712

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB3	ENST00000373366.3	TSL:1 MANE Select	c.652_663delCTGCACAAGGAC	p.Leu218_Asp221del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000362464.2	O75712
	GJB3	ENST00000373362.3	TSL:1	c.652_663delCTGCACAAGGAC	p.Leu218_Asp221del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000362460.3	O75712
	SMIM12	ENST00000426886.1	TSL:1	n.208-67015_208-67004delTCCTTGTGCAGG		intron	N/A	ENSP00000429902.1	E5RH51

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000279 AC: 70 AN: 251276 AF XY: 0.000250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000236 AC: 345 AN: 1461862 Hom.: 1 AF XY: 0.000237 AC XY: 172 AN XY: 727232

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53400

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5764

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1112008

Other (OTH) AF: 0.000662 AC: 40 AN: 60394

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74332

African (AFR) AF: 0.000121 AC: 5 AN: 41436

American (AMR) AF: 0.000327 AC: 5 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00316 AC: 1 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000521 Hom.: 1

Bravo AF: 0.000230

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 1A;C2675236:Autosomal dominant nonsyndromic hearing loss 2B;C4551486:Erythrokeratodermia variabilis et progressiva 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=186/14	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503069; hg19: chr1-35251013;