1-228158211-CGAGGAGGAG-CGAGGAG

Variant names:

• chr1-228158211-CGAG-C
• rs746050475
• NM_020435.4:c.472_474delGAG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3 BP6

The NM_020435.4(GJC2):​c.472_474delGAG​(p.Glu158del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,328,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (0 hom.)
• Consequence: GJC2 NM_020435.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_020435.4
• BP6: Variant 1-228158211-CGAG-C is Benign according to our data. Variant chr1-228158211-CGAG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 811586.

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.472_474delGAG	p.Glu158del	conservative_inframe_deletion	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.472_474delGAG	p.Glu158del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000355675.2	Q5T442
	GJC2	ENST00000886860.1		c.472_474delGAG	p.Glu158del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.472_474delGAG	p.Glu158del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes AF: 0.000187 AC: 28 AN: 149912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000513

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0826 AC: 3454 AN: 41820 AF XY: 0.0834

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0736

Gnomad ASJ exome AF: 0.0859

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.0832

Gnomad OTH exome AF: 0.0805

GnomAD4 exome AF: 0.00599 AC: 7063 AN: 1178354 Hom.: 0 AF XY: 0.00677 AC XY: 3866 AN XY: 570674

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

African (AFR) AF: 0.0124 AC: 325 AN: 26202

American (AMR) AF: 0.0311 AC: 737 AN: 23672

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 297 AN: 17712

East Asian (EAS) AF: 0.0144 AC: 396 AN: 27576

South Asian (SAS) AF: 0.0179 AC: 908 AN: 50670

European-Finnish (FIN) AF: 0.0102 AC: 241 AN: 23728

Middle Eastern (MID) AF: 0.00997 AC: 33 AN: 3310

European-Non Finnish (NFE) AF: 0.00394 AC: 3775 AN: 958108

Other (OTH) AF: 0.00741 AC: 351 AN: 47376

⚠️ 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 AF: 0.000187 AC: 28 AN: 149988 Hom.: 0 Cov.: 32 AF XY: 0.000219 AC XY: 16 AN XY: 73200

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

African (AFR) AF: 0.0000727 AC: 3 AN: 41246

American (AMR) AF: 0.000133 AC: 2 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.000513 AC: 5 AN: 9744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000208 AC: 14 AN: 67264

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0388 Hom.: 4

Asia WGS AF: 0.00783 AC: 27 AN: 3464

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	GJC2-related disorder (1)
-	-	1	not provided (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=79/21	polymorphism

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: rs746050475; hg19: chr1-228345912; COSMIC: COSV64512819;