1-228158705-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The ENST00000366714.3(GJC2):​c.947C>T​(p.Pro316Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,179,386 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. P316Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (7 hom.)
• Consequence: GJC2 ENST00000366714.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• 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: Benign. The variant received -12 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=0.011750877).
• BP6: Variant 1-228158705-C-T is Benign according to our data. Variant chr1-228158705-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235661.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00705 (1034/146612) while in subpopulation AFR AF = 0.0241 (984/40906). AF 95% confidence interval is 0.0228. There are 9 homozygotes in GnomAd4. There are 519 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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>T	p.Pro316Leu	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>T	p.Pro316Leu	missense	Exon 2 of 2	ENSP00000355675.2

Frequencies

GnomAD3 genomes AF: 0.00699 AC: 1025 AN: 146544 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00244

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0000303

Gnomad OTH AF: 0.00495

GnomAD2 exomes AF: 0.000915 AC: 16 AN: 17492 AF XY: 0.000467

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00167

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.000546 AC: 564 AN: 1032774 Hom.: 7 Cov.: 31 AF XY: 0.000512 AC XY: 255 AN XY: 498498

African (AFR) AF: 0.0258 AC: 482 AN: 18702

American (AMR) AF: 0.00239 AC: 18 AN: 7536

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 13422

South Asian (SAS) AF: 0.0000696 AC: 3 AN: 43112

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

Middle Eastern (MID) AF: 0.00122 AC: 3 AN: 2460

European-Non Finnish (NFE) AF: 0.0000148 AC: 13 AN: 880132

Other (OTH) AF: 0.00120 AC: 45 AN: 37614

GnomAD4 genome AF: 0.00705 AC: 1034 AN: 146612 Hom.: 9 Cov.: 32 AF XY: 0.00728 AC XY: 519 AN XY: 71340

African (AFR) AF: 0.0241 AC: 984 AN: 40906

American (AMR) AF: 0.00243 AC: 36 AN: 14794

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5066

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

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

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.0000303 AC: 2 AN: 66018

Other (OTH) AF: 0.00491 AC: 10 AN: 2038

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000463 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.32	N
PhyloP100		0.52
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.12	N
REVEL	Uncertain	0.61
Sift	Benign	0.17	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.15
MVP		0.58
ClinPred		0.0027	T
GERP RS		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.25
Mutation Taster		=89/11	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;