1-228157866-C-T

Variant names:

• chr1-228157866-C-T
• rs75469429
• NM_020435.4:c.108C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020435.4(GJC2):​c.108C>T​(p.Ile36Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,611,550 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (33 hom.)
• Consequence: GJC2 NM_020435.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.49
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-228157866-C-T is Benign according to our data. Variant chr1-228157866-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.011 (1682/152252) while in subpopulation AFR AF = 0.0386 (1603/41560). AF 95% confidence interval is 0.037. There are 40 homozygotes in GnomAd4. There are 795 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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.108C>T	p.Ile36Ile	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.108C>T	p.Ile36Ile	synonymous	Exon 2 of 2	ENSP00000355675.2
	GJC2	ENST00000886860.1		c.108C>T	p.Ile36Ile	synonymous	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.108C>T	p.Ile36Ile	synonymous	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1676 AN: 152144 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00293 AC: 717 AN: 244924 AF XY: 0.00210

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.00193

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000726

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00115 AC: 1673 AN: 1459298 Hom.: 33 Cov.: 37 AF XY: 0.00101 AC XY: 732 AN XY: 725770

African (AFR) AF: 0.0407 AC: 1363 AN: 33466

American (AMR) AF: 0.00213 AC: 95 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000256 AC: 22 AN: 85864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52196

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5762

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111412

Other (OTH) AF: 0.00234 AC: 141 AN: 60304

GnomAD4 genome AF: 0.0110 AC: 1682 AN: 152252 Hom.: 40 Cov.: 32 AF XY: 0.0107 AC XY: 795 AN XY: 74452

African (AFR) AF: 0.0386 AC: 1603 AN: 41560

American (AMR) AF: 0.00399 AC: 61 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67990

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00588 Hom.: 11

Bravo AF: 0.0124

Asia WGS AF: 0.00261 AC: 9 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.4
DANN	Benign	0.74
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs75469429; hg19: chr1-228345567;