1-228149860-A-G

Position:

• chr1-228149860-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: Unknown
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: -0.233

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-228149860-A-G is Pathogenic according to our data. Variant chr1-228149860-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 188 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 2 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jun 30, 2021	This variant (c.-167A>G, promoter region) has not been observed in population databases (gnomAD). The change has been reported in the literature (it has been shown to segregate with the condition), and functional studies indicate a decrease in protein expression (PMID 24374284, PMID 21246605, PMID 20695017, PMID 21959080, PMID 23242375). It was found as homozygous in affected individuals in two unrelated families, and heterozygous in another affected individual also heterozygous for c.893_942del (p.Val298Alafs*33, likely pathogenic), although no parental studies were performed. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 17, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects GJC2 function (PMID: 20695017, 21246605, 24374284). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 30759). This variant has been observed in individual(s) with Pelizaeus–Merzbacher-like disease (PMID: 20695017, 21246605, 21959080, 23142375). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the GJC2 gene. It does not change the encoded amino acid sequence of the GJC2 protein. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.92

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: rs587776888; hg19: chr1-228337561;