1-228158352-C-T

Variant names:

• chr1-228158352-C-T
• rs116557768
• NM_020435.4:c.594C>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.594C>T​(p.His198His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,588,150 control chromosomes in the GnomAD database, including 1,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (68 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1263 hom.)
• Consequence: GJC2 NM_020435.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.273
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 1-228158352-C-T is Benign according to our data. Variant chr1-228158352-C-T is described in ClinVar as Benign. ClinVar VariationId is 241298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.273 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0251 (3808/151878) while in subpopulation NFE AF = 0.0417 (2834/67902). AF 95% confidence interval is 0.0405. There are 68 homozygotes in GnomAd4. There are 1761 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 68 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.594C>T	p.His198His	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.594C>T	p.His198His	synonymous	Exon 2 of 2	ENSP00000355675.2
	GJC2	ENST00000886860.1		c.594C>T	p.His198His	synonymous	Exon 2 of 2	ENSP00000556919.1
	GJC2	ENST00000963922.1		c.594C>T	p.His198His	synonymous	Exon 2 of 2	ENSP00000633981.1

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3813 AN: 151764 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0385

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0294 AC: 6109 AN: 207860 AF XY: 0.0313

Gnomad AFR exome AF: 0.00642

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.000256

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.0418

Gnomad OTH exome AF: 0.0305

GnomAD4 exome AF: 0.0393 AC: 56385 AN: 1436272 Hom.: 1263 Cov.: 36 AF XY: 0.0396 AC XY: 28255 AN XY: 713512

African (AFR) AF: 0.00499 AC: 165 AN: 33084

American (AMR) AF: 0.0107 AC: 449 AN: 41942

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 601 AN: 25762

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38820

South Asian (SAS) AF: 0.0438 AC: 3713 AN: 84722

European-Finnish (FIN) AF: 0.0220 AC: 953 AN: 43328

Middle Eastern (MID) AF: 0.0233 AC: 129 AN: 5540

European-Non Finnish (NFE) AF: 0.0438 AC: 48372 AN: 1103496

Other (OTH) AF: 0.0335 AC: 1997 AN: 59578

GnomAD4 genome AF: 0.0251 AC: 3808 AN: 151878 Hom.: 68 Cov.: 32 AF XY: 0.0237 AC XY: 1761 AN XY: 74254

African (AFR) AF: 0.00715 AC: 297 AN: 41536

American (AMR) AF: 0.0106 AC: 162 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 100 AN: 3466

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5162

South Asian (SAS) AF: 0.0383 AC: 185 AN: 4824

European-Finnish (FIN) AF: 0.0162 AC: 168 AN: 10398

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0417 AC: 2834 AN: 67902

Other (OTH) AF: 0.0128 AC: 27 AN: 2104

Alfa AF: 0.0343 Hom.: 30

Bravo AF: 0.0229

Asia WGS AF: 0.0160 AC: 55 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	-0.51
CADD	Benign	8.5
DANN	Benign	0.60
PhyloP100		-0.27
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: rs116557768; hg19: chr1-228346053; COSMIC: COSV64512408;