chr1-228149857-A-G

Variant names:

• chr1-228149857-A-G
• rs587777496
• NM_020435.4:c.-170A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_020435.4(GJC2):​c.-170A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. 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: GJC2 NM_020435.4 upstream_gene
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 3.09
• Publications: 3 publications found

Genes affected

GJC2 (HGNC:17494): (gap junction protein gamma 2) This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. [provided by RefSeq, Jul 2008]

GJC2 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• lymphatic malformation 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hereditary spastic paraplegia 44

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• lymphatic malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 139577.
• 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 rank	MANE	Protein	UniProt
GJC2	NM_020435.4	c.-170A>G		upstream_gene_variant		ENST00000366714.3	NP_065168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3	c.-170A>G		upstream_gene_variant		1	NM_020435.4	ENSP00000355675.2

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

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 16

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 196

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

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

Jul 13, 2021

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 06, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Spastic paraplegia Uncertain:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of GJC2-related conditions (PMID: 24374284, 37267771). ClinVar contains an entry for this variant (Variation ID: 139577). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GJC2 function (PMID: 24374284). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.91
PhyloP100		3.1
PromoterAI		-0.056	Neutral
Mutation Taster		=111/189	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777496; hg19: chr1-228337558;