1-228158333-C-G

Variant names:

• chr1-228158333-C-G
• rs375318012
• NM_020435.4:c.575C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_020435.4(GJC2):​c.575C>G​(p.Pro192Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,564,994 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P192L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: GJC2 NM_020435.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.479
• 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: Benign. The variant received -8 ACMG points.

• 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=0.01837939).
• BP6: Variant 1-228158333-C-G is Benign according to our data. Variant chr1-228158333-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 429631.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.575C>G	p.Pro192Arg	missense	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.575C>G	p.Pro192Arg	missense	Exon 2 of 2	ENSP00000355675.2
	GJC2	ENST00000886860.1		c.575C>G	p.Pro192Arg	missense	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.575C>G	p.Pro192Arg	missense	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000287

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00118 AC: 206 AN: 174694 AF XY: 0.00124

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000938

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.00151 AC: 2129 AN: 1413048 Hom.: 3 Cov.: 36 AF XY: 0.00149 AC XY: 1040 AN XY: 699918

African (AFR) AF: 0.000215 AC: 7 AN: 32496

American (AMR) AF: 0.000130 AC: 5 AN: 38442

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25406

East Asian (EAS) AF: 0.00 AC: 0 AN: 37376

South Asian (SAS) AF: 0.00115 AC: 95 AN: 82912

European-Finnish (FIN) AF: 0.000194 AC: 8 AN: 41244

Middle Eastern (MID) AF: 0.000190 AC: 1 AN: 5264

European-Non Finnish (NFE) AF: 0.00178 AC: 1945 AN: 1091202

Other (OTH) AF: 0.00114 AC: 67 AN: 58706

GnomAD4 genome AF: 0.00109 AC: 166 AN: 151946 Hom.: 0 Cov.: 32 AF XY: 0.000969 AC XY: 72 AN XY: 74288

African (AFR) AF: 0.000409 AC: 17 AN: 41542

American (AMR) AF: 0.000392 AC: 6 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.000287 AC: 3 AN: 10454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 67894

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.000918

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00145 AC: 12

ExAC AF: 0.00112 AC: 131

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	4	not provided (7)
-	-	1	GJC2-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	3.7
DANN	Benign	0.92
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.7	L
PhyloP100		-0.48
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.21
Sift	Benign	0.092	T
Sift4G	Benign	0.24	T
Polyphen		0.049	B
Vest4		0.20
MVP		0.52
ClinPred		0.023	T
GERP RS		-4.0
Varity_R		0.061
gMVP		0.29
Mutation Taster		=92/8	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: rs375318012; hg19: chr1-228346034; COSMIC: COSV100813030;