chr5-113534404-C-T

Position:

• chr5-113534404-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_022828.5(YTHDC2):​c.942C>T​(p.Ile314Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,608,082 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (11 hom.)
• Consequence: YTHDC2 NM_022828.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.69

Genes affected

YTHDC2 (HGNC:24721): (YTH N6-methyladenosine RNA binding protein C2) This gene encodes a member of the DEAH (Asp-Glu-Ala-His) subfamily of proteins, part of the DEAD (Asp-Glu-Ala-Asp) box family of RNA helicases. The encoded protein binds to N6-methyladenosine, a common modified RNA nucleotide that is enriched in the stop codons and 3' UTRs of eukaryotic messenger RNAs. Binding of proteins to this modified nucleotide may regulate mRNA translation and stability. This gene may be associated with susceptibility to pancreatic cancer in human patients, and knockdown of this gene resulted in reduced proliferation in a human liver cancer cell line. [provided by RefSeq, Sep 2016]

YTHDC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 5-113534404-C-T is Benign according to our data. Variant chr5-113534404-C-T is described in ClinVar as [Benign]. Clinvar id is 776058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.69 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0065 (988/151956) while in subpopulation AFR AF= 0.022 (912/41432). AF 95% confidence interval is 0.0208. There are 7 homozygotes in gnomad4. There are 468 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 988 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YTHDC2	NM_022828.5	c.942C>T	p.Ile314Ile	synonymous_variant	6/30	ENST00000161863.9	NP_073739.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YTHDC2	ENST00000161863.9	c.942C>T	p.Ile314Ile	synonymous_variant	6/30	1	NM_022828.5	ENSP00000161863.4
YTHDC2	ENST00000515883.5	c.942C>T	p.Ile314Ile	synonymous_variant	6/17	1		ENSP00000423101.1
YTHDC2	ENST00000503857.5	n.*248C>T		non_coding_transcript_exon_variant	4/16	5		ENSP00000426644.1
YTHDC2	ENST00000503857.5	n.*248C>T		3_prime_UTR_variant	4/16	5		ENSP00000426644.1

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 988 AN: 151838 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00577

GnomAD3 exomes AF: 0.00175 AC: 439 AN: 251296 Hom.: 3 AF XY: 0.00140 AC XY: 190 AN XY: 135828

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000696 AC: 1013 AN: 1456126 Hom.: 11 Cov.: 29 AF XY: 0.000639 AC XY: 463 AN XY: 724410

Gnomad4 AFR exome AF: 0.0223

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00650 AC: 988 AN: 151956 Hom.: 7 Cov.: 32 AF XY: 0.00630 AC XY: 468 AN XY: 74242

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00571

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00768

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

YTHDC2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs77180725; hg19: chr5-112870101; COSMIC: COSV104550716;