6-30704212-G-C

Variant names:

• chr6-30704212-G-C
• rs28986317
• NM_014641.3:c.4971C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_014641.3(MDC1):​c.4971C>G​(p.Ala1657Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,613,798 control chromosomes in the GnomAD database, including 3,494 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.053 (262 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3232 hom.)
• Consequence: MDC1 NM_014641.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 14 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]

MDC1-AS1 (HGNC:39764): (MDC1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014641.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	NM_014641.3	MANE Select	c.4971C>G	p.Ala1657Ala	synonymous	Exon 10 of 15	NP_055456.2
	MDC1-AS1	NR_133647.1		n.127+1019G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	ENST00000376406.8	TSL:5 MANE Select	c.4971C>G	p.Ala1657Ala	synonymous	Exon 10 of 15	ENSP00000365588.3
	MDC1-AS1	ENST00000442150.1	TSL:3	n.127+1019G>C		intron	N/A
	MDC1	ENST00000489540.1	TSL:2	n.-131C>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8060 AN: 152086 Hom.: 262 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.0392

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.0172

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0624

Gnomad OTH AF: 0.0584

GnomAD2 exomes AF: 0.0559 AC: 14022 AN: 251042 AF XY: 0.0598

Gnomad AFR exome AF: 0.0419

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.0980

Gnomad EAS exome AF: 0.0103

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0601

Gnomad OTH exome AF: 0.0582

GnomAD4 exome AF: 0.0619 AC: 90470 AN: 1461594 Hom.: 3232 Cov.: 35 AF XY: 0.0636 AC XY: 46236 AN XY: 727094

African (AFR) AF: 0.0471 AC: 1577 AN: 33470

American (AMR) AF: 0.0310 AC: 1384 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0967 AC: 2523 AN: 26104

East Asian (EAS) AF: 0.00804 AC: 319 AN: 39690

South Asian (SAS) AF: 0.111 AC: 9574 AN: 86228

European-Finnish (FIN) AF: 0.0234 AC: 1249 AN: 53414

Middle Eastern (MID) AF: 0.0953 AC: 549 AN: 5760

European-Non Finnish (NFE) AF: 0.0624 AC: 69356 AN: 1111838

Other (OTH) AF: 0.0652 AC: 3939 AN: 60382

GnomAD4 genome AF: 0.0529 AC: 8054 AN: 152204 Hom.: 262 Cov.: 32 AF XY: 0.0528 AC XY: 3929 AN XY: 74402

African (AFR) AF: 0.0430 AC: 1785 AN: 41526

American (AMR) AF: 0.0392 AC: 599 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 330 AN: 3472

East Asian (EAS) AF: 0.0172 AC: 89 AN: 5176

South Asian (SAS) AF: 0.108 AC: 520 AN: 4816

European-Finnish (FIN) AF: 0.0245 AC: 260 AN: 10602

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0625 AC: 4248 AN: 68004

Other (OTH) AF: 0.0578 AC: 122 AN: 2110

Alfa AF: 0.0511 Hom.: 106

Bravo AF: 0.0524

Asia WGS AF: 0.0520 AC: 184 AN: 3478

EpiCase AF: 0.0684

EpiControl AF: 0.0658

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.80
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28986317; hg19: chr6-30671989; COSMIC: COSV64526914; COSMIC: COSV64526914;