1-228158705-C-G

Variant names:

• chr1-228158705-C-G
• rs760502262
• NM_020435.4:c.947C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000366714.3(GJC2):​c.947C>G​(p.Pro316Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,179,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P316L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 9.7e-7 (0 hom.)
• Consequence: GJC2 ENST00000366714.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.518
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.8719 (below the threshold of 3.09). Trascript score misZ: -1.3976 (below the threshold of 3.09). GenCC associations: The gene is linked to hypomyelinating leukodystrophy 2, hereditary spastic paraplegia 44, lymphatic malformation 3, lymphatic malformation.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19180027).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366714.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	NM_020435.4	MANE Select	c.947C>G	p.Pro316Arg	missense	Exon 2 of 2	NP_065168.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJC2	ENST00000366714.3	TSL:1 MANE Select	c.947C>G	p.Pro316Arg	missense	Exon 2 of 2	ENSP00000355675.2

Frequencies

GnomAD3 genomes AF: 0.00000682 AC: 1 AN: 146544 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.68e-7 AC: 1 AN: 1032780 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 498502

African (AFR) AF: 0.00 AC: 0 AN: 18706

American (AMR) AF: 0.00 AC: 0 AN: 7536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11022

East Asian (EAS) AF: 0.00 AC: 0 AN: 13424

South Asian (SAS) AF: 0.00 AC: 0 AN: 43112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18774

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2460

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 880132

Other (OTH) AF: 0.00 AC: 0 AN: 37614

GnomAD4 genome AF: 0.00000682 AC: 1 AN: 146544 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71260

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

African (AFR) AF: 0.00 AC: 0 AN: 40806

American (AMR) AF: 0.00 AC: 0 AN: 14778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66028

Other (OTH) AF: 0.00 AC: 0 AN: 2020

⚠️ 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: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.4	L
PhyloP100		0.52
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.34
Sift	Benign	0.12	T
Sift4G	Benign	0.34	T
Polyphen		0.18	B
Vest4		0.16
MutPred		0.30		Loss of glycosylation at P316 (P = 0.0022)
MVP		0.66
ClinPred		0.17	T
GERP RS		-0.86
Varity_R		0.13
gMVP		0.25
Mutation Taster		=87/13	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: rs760502262; hg19: chr1-228346406;