chr1-228157826-T-TGGGCAAGGTGTGGC

Variant names:

• chr1-228157826-T-TGGGCAAGGTGTGGC
• NM_020435.4:c.69_82dupGGGCAAGGTGTGGC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_020435.4(GJC2):​c.69_82dupGGGCAAGGTGTGGC​(p.Leu28ArgfsTer16) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000727 in 1,375,804 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L28L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: GJC2 NM_020435.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.68
• Publications: 0 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: Ambry Genetics, G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• lymphatic malformation 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 77 pathogenic variants in the truncated region.
• PP5: Variant 1-228157826-T-TGGGCAAGGTGTGGC is Pathogenic according to our data. Variant chr1-228157826-T-TGGGCAAGGTGTGGC is described in ClinVar as Pathogenic. ClinVar VariationId is 2726006.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020435.4. 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
	GJC2	NM_020435.4	MANE Select	c.69_82dupGGGCAAGGTGTGGC	p.Leu28ArgfsTer16	frameshift	Exon 2 of 2	NP_065168.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	ENST00000366714.3	TSL:1 MANE Select	c.69_82dupGGGCAAGGTGTGGC	p.Leu28ArgfsTer16	frameshift	Exon 2 of 2	ENSP00000355675.2	Q5T442
	GJC2	ENST00000886860.1		c.69_82dupGGGCAAGGTGTGGC	p.Leu28ArgfsTer16	frameshift	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.69_82dupGGGCAAGGTGTGGC	p.Leu28ArgfsTer16	frameshift	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375804 Hom.: 0 Cov.: 37 AF XY: 0.00000147 AC XY: 1 AN XY: 682576

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31204

American (AMR) AF: 0.00 AC: 0 AN: 41260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22988

East Asian (EAS) AF: 0.00 AC: 0 AN: 32646

South Asian (SAS) AF: 0.00 AC: 0 AN: 83890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5326

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058320

Other (OTH) AF: 0.00 AC: 0 AN: 54810

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=2/198	disease causing

Splicing

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

Other links and lift over

hg19: chr1-228345527;