1-228158211-CGAGGAGGAG-CGAGGAGGAGGAGGAGGAG

Variant names:

• chr1-228158211-C-CGAGGAGGAG
• rs746050475
• NM_020435.4:c.466_474dupGAGGAGGAG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP3

The NM_020435.4(GJC2):​c.466_474dupGAGGAGGAG​(p.Glu156_Glu158dup) variant causes a conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000451 in 1,330,008 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: GJC2 NM_020435.4 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.06
• Publications: 2 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 0 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP3: Nonframeshift variant in repetitive region in NM_020435.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJC2	NM_020435.4	c.466_474dupGAGGAGGAG	p.Glu156_Glu158dup	conservative_inframe_insertion	Exon 2 of 2	ENST00000366714.3	NP_065168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3	c.466_474dupGAGGAGGAG	p.Glu156_Glu158dup	conservative_inframe_insertion	Exon 2 of 2	1	NM_020435.4	ENSP00000355675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000451 AC: 6 AN: 1330008 Hom.: 0 Cov.: 35 AF XY: 0.00000461 AC XY: 3 AN XY: 651146

African (AFR) AF: 0.00 AC: 0 AN: 29748

American (AMR) AF: 0.00 AC: 0 AN: 30366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21794

East Asian (EAS) AF: 0.00 AC: 0 AN: 34350

South Asian (SAS) AF: 0.00 AC: 0 AN: 71042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31954

Middle Eastern (MID) AF: 0.000516 AC: 2 AN: 3874

European-Non Finnish (NFE) AF: 0.00000380 AC: 4 AN: 1051670

Other (OTH) AF: 0.00 AC: 0 AN: 55210

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 4

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=80/20	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs746050475; hg19: chr1-228345912;