NM_020435.4:c.1234C>T

Variant names:

• chr1-228158992-C-T
• rs200334298
• NM_020435.4:c.1234C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_020435.4(GJC2):​c.1234C>T​(p.His412Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000956 in 1,603,620 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (3 hom.)
• Consequence: GJC2 NM_020435.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3
• Conservation: PhyloP100: 4.83
• Publications: 4 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: Likely_benign. The variant received -5 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=0.089141846).
• 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.1234C>T	p.His412Tyr	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.1234C>T	p.His412Tyr	missense	Exon 2 of 2	ENSP00000355675.2
	GJC2	ENST00000886860.1		c.1234C>T	p.His412Tyr	missense	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.1234C>T	p.His412Tyr	missense	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000748 AC: 169 AN: 225966 AF XY: 0.000719

Gnomad AFR exome AF: 0.0000805

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.000629

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000428

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000715

GnomAD4 exome AF: 0.000959 AC: 1392 AN: 1451458 Hom.: 3 Cov.: 33 AF XY: 0.000938 AC XY: 677 AN XY: 721648

African (AFR) AF: 0.000150 AC: 5 AN: 33274

American (AMR) AF: 0.000225 AC: 10 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.000655 AC: 17 AN: 25966

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85434

European-Finnish (FIN) AF: 0.000801 AC: 40 AN: 49916

Middle Eastern (MID) AF: 0.000713 AC: 3 AN: 4206

European-Non Finnish (NFE) AF: 0.00114 AC: 1260 AN: 1109032

Other (OTH) AF: 0.000920 AC: 55 AN: 59772

GnomAD4 genome AF: 0.000927 AC: 141 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.000700 AC XY: 52 AN XY: 74324

African (AFR) AF: 0.000217 AC: 9 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68000

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.000971

ExAC AF: 0.000797 AC: 89

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
-	1	1	not specified (2)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Hypomyelinating leukodystrophy 2 (1)
-	1	-	Hypomyelinating leukodystrophy 2;C2750784:Hereditary spastic paraplegia 44;C4747646:Lymphatic malformation 3 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.089	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.34	N
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.50
Sift	Benign	0.037	D
Sift4G	Uncertain	0.058	T
Polyphen		0.10	B
Vest4		0.71
MVP		0.93
ClinPred		0.047	T
GERP RS		2.9
Varity_R		0.16
gMVP		0.12
Mutation Taster		=29/71	disease causing

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: rs200334298; hg19: chr1-228346693;