6-30700597-G-A

Variant names:

• chr6-30700597-G-A
• rs9468812
• NM_014641.3:c.6138C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_014641.3(MDC1):​c.6138C>T​(p.Phe2046Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,612,902 control chromosomes in the GnomAD database, including 690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (298 hom., cov: 31)
  • Exomes 𝑓: 0.013 (392 hom.)
• Consequence: MDC1 NM_014641.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.676
• Publications: 2 publications found

Genes affected

MDC1 (HGNC:21163): (mediator of DNA damage checkpoint 1) The protein encoded by this gene contains an N-terminal forkhead domain, two BRCA1 C-terminal (BRCT) motifs and a central domain with 13 repetitions of an approximately 41-amino acid sequence. The encoded protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. This nuclear protein interacts with phosphorylated histone H2AX near sites of DNA double-strand breaks through its BRCT motifs, and facilitates recruitment of the ATM kinase and meiotic recombination 11 protein complex to DNA damage foci. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 6-30700597-G-A is Benign according to our data. Variant chr6-30700597-G-A is described in ClinVar as [Benign]. Clinvar id is 1265487.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.676 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDC1	NM_014641.3	c.6138C>T	p.Phe2046Phe	synonymous_variant	Exon 15 of 15	ENST00000376406.8	NP_055456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDC1	ENST00000376406.8	c.6138C>T	p.Phe2046Phe	synonymous_variant	Exon 15 of 15	5	NM_014641.3	ENSP00000365588.3
MDC1	ENST00000489540.1	n.1120C>T		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.0410 AC: 6229 AN: 152052 Hom.: 299 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0356

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00903

Gnomad OTH AF: 0.0464

GnomAD2 exomes AF: 0.0200 AC: 4927 AN: 245976 AF XY: 0.0180

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0509

Gnomad EAS exome AF: 0.0144

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0234

GnomAD4 exome AF: 0.0132 AC: 19258 AN: 1460732 Hom.: 392 Cov.: 31 AF XY: 0.0126 AC XY: 9143 AN XY: 726686

African (AFR) AF: 0.122 AC: 4076 AN: 33474

American (AMR) AF: 0.0277 AC: 1238 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 1272 AN: 26136

East Asian (EAS) AF: 0.0351 AC: 1394 AN: 39700

South Asian (SAS) AF: 0.00408 AC: 352 AN: 86258

European-Finnish (FIN) AF: 0.00162 AC: 85 AN: 52312

Middle Eastern (MID) AF: 0.0222 AC: 128 AN: 5768

European-Non Finnish (NFE) AF: 0.00859 AC: 9550 AN: 1111980

Other (OTH) AF: 0.0193 AC: 1163 AN: 60380

GnomAD4 genome AF: 0.0410 AC: 6237 AN: 152170 Hom.: 298 Cov.: 31 AF XY: 0.0395 AC XY: 2939 AN XY: 74386

African (AFR) AF: 0.113 AC: 4703 AN: 41478

American (AMR) AF: 0.0356 AC: 544 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3468

East Asian (EAS) AF: 0.0177 AC: 92 AN: 5190

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10612

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00903 AC: 614 AN: 68000

Other (OTH) AF: 0.0459 AC: 97 AN: 2112

Alfa AF: 0.0194 Hom.: 173

Bravo AF: 0.0485

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0133

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 14, 2020

GeneDx

Significance: 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	-0.67
CADD	Benign	2.4
DANN	Benign	0.75
PhyloP100		-0.68
Mutation Taster		=99/1	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: rs9468812; hg19: chr6-30668374;