rs9262152

Positions:

• chr6-30713139-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDC1	NM_014641.3	c.803G>A	p.Arg268Lys	missense_variant	5/15	ENST00000376406.8
MDC1-AS1	NR_133647.1	n.693C>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDC1	ENST00000376406.8	c.803G>A	p.Arg268Lys	missense_variant	5/15	5	NM_014641.3	P1
MDC1-AS1	ENST00000442150.1	n.693C>T		non_coding_transcript_exon_variant	3/3	3

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

GnomAD3 exomes AF: 0.149 AC: 36652 AN: 246588 Hom.: 3091 AF XY: 0.154 AC XY: 20732 AN XY: 134342

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 SAS exome AF: 0.203

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

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.0567

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.150

Gnomad4 OTH exome AF: 0.142

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

Gnomad4 AFR AF: 0.0291

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.106

Gnomad4 EAS AF: 0.0637

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.127

Alfa AF: 0.149 Hom.: 4044

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 v4.3

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
MutationTaster	Benign	1.0	P;P
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

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: rs9262152; hg19: chr6-30680916; COSMIC: COSV64529451; COSMIC: COSV64529451;