rs587777496

Positions:

• chr1-228149857-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: Unknown
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 3.09

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-228149857-A-G is Pathogenic according to our data. Variant chr1-228149857-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139577.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41). . 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: 228 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 172

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: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypomyelinating leukodystrophy 2 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 06, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 13, 2021	This variant (c.-170A>G, promoter region) has not been observed in population databases (gnomAD). The change has been reported in the literature, and functional studies indicate a decrease in protein expression (PMID 24374284). It was found to be homozygous in two unrelated affected individuals, and heterozygous in one unaffected sibling. -

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 19, 2022

This variant has been observed in individuals with Pelizaeus-Merzbacher-like disease (PMID: 24374284). 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. ClinVar contains an entry for this variant (Variation ID: 139577). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant affects GJC2 function (PMID: 24374284). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.91

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: rs587777496; hg19: chr1-228337558;