NM_020435.4:c.17G>A

Variant names:

• chr1-228157775-G-A
• rs878853083
• NM_020435.4:c.17G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020435.4(GJC2):​c.17G>A​(p.Trp6*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,015,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: GJC2 NM_020435.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.63
• 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 18 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 82 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-228157775-G-A is Pathogenic according to our data. Variant chr1-228157775-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 235629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.17G>A	p.Trp6*	stop_gained	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.17G>A	p.Trp6*	stop_gained	Exon 2 of 2	ENSP00000355675.2	Q5T442
	GJC2	ENST00000886860.1		c.17G>A	p.Trp6*	stop_gained	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.17G>A	p.Trp6*	stop_gained	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes AF: 0.0000165 AC: 2 AN: 121398 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000112 AC: 1 AN: 893988 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 442100

⚠️ 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: 19592

American (AMR) AF: 0.00 AC: 0 AN: 27672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14298

East Asian (EAS) AF: 0.00 AC: 0 AN: 11086

South Asian (SAS) AF: 0.00 AC: 0 AN: 71128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2632

European-Non Finnish (NFE) AF: 0.00000145 AC: 1 AN: 687752

Other (OTH) AF: 0.00 AC: 0 AN: 32888

⚠️ 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: 0.0000165 AC: 2 AN: 121398 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 56136

African (AFR) AF: 0.0000628 AC: 2 AN: 31856

American (AMR) AF: 0.00 AC: 0 AN: 9080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3266

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 3588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 200

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62332

Other (OTH) AF: 0.00 AC: 0 AN: 1682

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hypomyelinating leukodystrophy 2 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	41
DANN	Uncertain	0.98
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.6
Vest4		0.66
GERP RS		3.1
Mutation Taster		=19/181	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs878853083; hg19: chr1-228345476;