8-74350062-C-A

Variant names:

• chr8-74350062-C-A
• rs78334365
• ENST00000521872.2:n.255G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000521872.2(ENSG00000253596):​n.255G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 238,832 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: ENSG00000253596 ENST00000521872.2 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.500
• Publications: 0 publications found

Genes affected

ENSG00000253596 (HGNC:):

GDAP1 (HGNC:15968): (ganglioside induced differentiation associated protein 1) This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]

GDAP1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2K

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease recessive intermediate A

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant Charcot-Marie-Tooth disease type 2K

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Charcot-Marie-Tooth disease type 4A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 8-74350062-C-A is Benign according to our data. Variant chr8-74350062-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1193047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0082 (1249/152282) while in subpopulation AFR AF = 0.0281 (1170/41566). AF 95% confidence interval is 0.0268. There are 20 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000253596	ENST00000521872.2	n.255G>T		non_coding_transcript_exon_variant	Exon 1 of 2	3
GDAP1	ENST00000674612.1	c.-17-10075C>A		intron_variant	Intron 1 of 4			ENSP00000501864.1
GDAP1	ENST00000675220.1	c.-17-10075C>A		intron_variant	Intron 1 of 4			ENSP00000502588.1

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1248 AN: 152164 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.000393 AC: 34 AN: 86550 Hom.: 0 Cov.: 0 AF XY: 0.000245 AC XY: 11 AN XY: 44926

African (AFR) AF: 0.0149 AC: 25 AN: 1674

American (AMR) AF: 0.00103 AC: 4 AN: 3876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2042

East Asian (EAS) AF: 0.00 AC: 0 AN: 3498

South Asian (SAS) AF: 0.00 AC: 0 AN: 13748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4874

Middle Eastern (MID) AF: 0.00321 AC: 1 AN: 312

European-Non Finnish (NFE) AF: 0.0000385 AC: 2 AN: 52012

Other (OTH) AF: 0.000443 AC: 2 AN: 4514

GnomAD4 genome AF: 0.00820 AC: 1249 AN: 152282 Hom.: 20 Cov.: 32 AF XY: 0.00755 AC XY: 562 AN XY: 74456

African (AFR) AF: 0.0281 AC: 1170 AN: 41566

American (AMR) AF: 0.00418 AC: 64 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.0146 Hom.: 3

Bravo AF: 0.00923

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.1
DANN	Benign	0.77
PhyloP100		-0.50
PromoterAI		-0.041	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78334365; hg19: chr8-75262297;