6-30713139-C-T

Variant names:

• chr6-30713139-C-T
• rs9262152
• NM_014641.3:c.803G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014641.3(MDC1):​c.803G>A​(p.Arg268Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,612,712 control chromosomes in the GnomAD database, including 18,416 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1371 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17045 hom.)
• Consequence: MDC1 NM_014641.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.57
• Publications: 48 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010517836).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.185 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.803G>A	p.Arg268Lys	missense	Exon 5 of 15	NP_055456.2
	MDC1-AS1	NR_133647.1		n.693C>T		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	ENST00000376406.8	TSL:5 MANE Select	c.803G>A	p.Arg268Lys	missense	Exon 5 of 15	ENSP00000365588.3
	MDC1	ENST00000939654.1		c.803G>A	p.Arg268Lys	missense	Exon 6 of 16	ENSP00000609713.1
	MDC1	ENST00000939657.1		c.803G>A	p.Arg268Lys	missense	Exon 5 of 14	ENSP00000609716.1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17860 AN: 152112 Hom.: 1371 Cov.: 32

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0636

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.149 AC: 36652 AN: 246588 AF XY: 0.154

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.163

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0540

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.148 AC: 215928 AN: 1460482 Hom.: 17045 Cov.: 38 AF XY: 0.150 AC XY: 109335 AN XY: 726502

African (AFR) AF: 0.0216 AC: 722 AN: 33474

American (AMR) AF: 0.164 AC: 7328 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2989 AN: 26110

East Asian (EAS) AF: 0.0567 AC: 2249 AN: 39696

South Asian (SAS) AF: 0.200 AC: 17271 AN: 86244

European-Finnish (FIN) AF: 0.174 AC: 9096 AN: 52376

Middle Eastern (MID) AF: 0.153 AC: 883 AN: 5766

European-Non Finnish (NFE) AF: 0.150 AC: 166844 AN: 1111740

Other (OTH) AF: 0.142 AC: 8546 AN: 60370

GnomAD4 genome AF: 0.117 AC: 17869 AN: 152230 Hom.: 1371 Cov.: 32 AF XY: 0.119 AC XY: 8849 AN XY: 74422

African (AFR) AF: 0.0291 AC: 1209 AN: 41556

American (AMR) AF: 0.147 AC: 2253 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3466

East Asian (EAS) AF: 0.0637 AC: 330 AN: 5178

South Asian (SAS) AF: 0.196 AC: 944 AN: 4828

European-Finnish (FIN) AF: 0.166 AC: 1756 AN: 10586

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10496 AN: 68014

Other (OTH) AF: 0.127 AC: 266 AN: 2102

Alfa AF: 0.143 Hom.: 7812

Bravo AF: 0.111

TwinsUK AF: 0.149 AC: 552

ALSPAC AF: 0.139 AC: 536

ESP6500AA AF: 0.0318 AC: 96

ESP6500EA AF: 0.158 AC: 857

ExAC AF: 0.146 AC: 17308

Asia WGS AF: 0.122 AC: 422 AN: 3478

EpiCase AF: 0.171

EpiControl AF: 0.166

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.63
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.6
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.044
Sift	Benign	0.45	T
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.018
MPC		0.20
ClinPred		0.0020	T
GERP RS		-2.1
Varity_R		0.088
gMVP		0.084
Mutation Taster		=98/2	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: rs9262152; hg19: chr6-30680916; COSMIC: COSV64529451; COSMIC: COSV64529451;