rs4653910

Variant names:

• chr1-228158724-G-C
• rs4653910
• NM_020435.4:c.966G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-228158724-G-C
• chr1-228158724-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020435.4(GJC2):​c.966G>C​(p.Ala322Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 1,318,888 control chromosomes in the GnomAD database, including 1,366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (220 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1146 hom.)
• Consequence: GJC2 NM_020435.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.222
• 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: 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-228158724-G-C is Benign according to our data. Variant chr1-228158724-G-C is described in ClinVar as Benign. ClinVar VariationId is 261257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.222 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

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.966G>C	p.Ala322Ala	synonymous	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.966G>C	p.Ala322Ala	synonymous	Exon 2 of 2	ENSP00000355675.2	Q5T442
	GJC2	ENST00000886860.1		c.966G>C	p.Ala322Ala	synonymous	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.966G>C	p.Ala322Ala	synonymous	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes AF: 0.0505 AC: 7430 AN: 147044 Hom.: 221 Cov.: 32

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.0277

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.0421

Gnomad FIN AF: 0.0630

Gnomad MID AF: 0.0419

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0444

GnomAD2 exomes AF: 0.0411 AC: 1910 AN: 46506 AF XY: 0.0392

Gnomad AFR exome AF: 0.0411

Gnomad AMR exome AF: 0.0491

Gnomad ASJ exome AF: 0.0423

Gnomad EAS exome AF: 0.0854

Gnomad FIN exome AF: 0.0581

Gnomad NFE exome AF: 0.0388

Gnomad OTH exome AF: 0.0335

GnomAD4 exome AF: 0.0414 AC: 48541 AN: 1171768 Hom.: 1146 Cov.: 32 AF XY: 0.0414 AC XY: 23797 AN XY: 575352

African (AFR) AF: 0.0535 AC: 1145 AN: 21420

American (AMR) AF: 0.0528 AC: 801 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.0454 AC: 750 AN: 16532

East Asian (EAS) AF: 0.115 AC: 2107 AN: 18304

South Asian (SAS) AF: 0.0335 AC: 2109 AN: 62880

European-Finnish (FIN) AF: 0.0585 AC: 1562 AN: 26704

Middle Eastern (MID) AF: 0.0261 AC: 82 AN: 3136

European-Non Finnish (NFE) AF: 0.0393 AC: 37834 AN: 962476

Other (OTH) AF: 0.0476 AC: 2151 AN: 45142

GnomAD4 genome AF: 0.0505 AC: 7428 AN: 147120 Hom.: 220 Cov.: 32 AF XY: 0.0523 AC XY: 3745 AN XY: 71658

African (AFR) AF: 0.0559 AC: 2286 AN: 40878

American (AMR) AF: 0.0505 AC: 750 AN: 14842

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 146 AN: 3400

East Asian (EAS) AF: 0.124 AC: 628 AN: 5066

South Asian (SAS) AF: 0.0419 AC: 201 AN: 4796

European-Finnish (FIN) AF: 0.0630 AC: 545 AN: 8650

Middle Eastern (MID) AF: 0.0350 AC: 10 AN: 286

European-Non Finnish (NFE) AF: 0.0415 AC: 2747 AN: 66252

Other (OTH) AF: 0.0440 AC: 90 AN: 2046

Alfa AF: 0.0216 Hom.: 14

Asia WGS AF: 0.0630 AC: 168 AN: 2688

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.35
PhyloP100		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs4653910; hg19: chr1-228346425; COSMIC: COSV64512933;