6-30703452-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_014641.3(MDC1):c.5648G>A(p.Arg1883Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,613,946 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.017 ( 27 hom., cov: 32)

Exomes 𝑓: 0.022 ( 418 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.523

Publications

13 publications found

Variant links:

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 links:

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

MDC1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060301423).

BP6

Variant 6-30703452-C-T is Benign according to our data. Variant chr6-30703452-C-T is described in ClinVar as Benign. ClinVar VariationId is 2656340.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2513/152236) while in subpopulation NFE AF = 0.025 (1697/68010). AF 95% confidence interval is 0.024. There are 27 homozygotes in GnomAd4. There are 1218 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	NM_014641.3	MANE Select	c.5648G>A	p.Arg1883Gln	missense	Exon 11 of 15	NP_055456.2	Q14676-1
	MDC1-AS1	NR_133647.1		n.127+259C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDC1	ENST00000376406.8	TSL:5 MANE Select	c.5648G>A	p.Arg1883Gln	missense	Exon 11 of 15	ENSP00000365588.3	Q14676-1
MDC1	ENST00000939654.1		c.5648G>A	p.Arg1883Gln	missense	Exon 12 of 16	ENSP00000609713.1
MDC1	ENST00000939657.1		c.5648G>A	p.Arg1883Gln	missense	Exon 11 of 14	ENSP00000609716.1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2514

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00481

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0154

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0249

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0173

AC:

4296

AN:

248952

AF XY:

0.0181

show subpopulations

Gnomad AFR exome

AF:

0.00291

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.00898

Gnomad EAS exome

AF:

0.00174

Gnomad FIN exome

AF:

0.0181

Gnomad NFE exome

AF:

0.0251

Gnomad OTH exome

AF:

0.0193

GnomAD4 exome

AF:

0.0216

AC:

31566

AN:

1461710

Hom.:

418

Cov.:

AF XY:

0.0218

AC XY:

15844

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00442

AC:

148

AN:

33480

American (AMR)

AF:

0.0123

AC:

549

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

295

AN:

26136

East Asian (EAS)

AF:

0.000730

AC:

AN:

39700

South Asian (SAS)

AF:

0.0151

AC:

1301

AN:

86258

European-Finnish (FIN)

AF:

0.0194

AC:

1035

AN:

53240

Middle Eastern (MID)

AF:

0.0270

AC:

156

AN:

5768

European-Non Finnish (NFE)

AF:

0.0242

AC:

26940

AN:

1112012

Other (OTH)

AF:

0.0184

AC:

1113

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

2080

4161

6241

8322

10402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

984

1968

2952

3936

4920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0165

AC:

2513

AN:

152236

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1218

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00477

AC:

198

AN:

41528

American (AMR)

AF:

0.0186

AC:

285

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3468

East Asian (EAS)

AF:

0.00154

AC:

AN:

5184

South Asian (SAS)

AF:

0.0108

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0154

AC:

163

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0250

AC:

1697

AN:

68010

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

123

246

370

493

616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0218

Hom.:

148

Bravo

AF:

0.0168

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00496

AC:

ESP6500EA

AF:

0.0196

AC:

106

ExAC

AF:

0.0178

AC:

2161

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0252

EpiControl

AF:

0.0261

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

0.042

Eigen_PC

Benign

-0.087

FATHMM_MKL

Benign

0.16

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.96

MutationAssessor

Pathogenic

3.1

PhyloP100

0.52

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.3

REVEL

Benign

0.22

Sift

Uncertain

0.020

Sift4G

Uncertain

0.048

Polyphen

1.0

Vest4

0.059

MPC

0.29

ClinPred

0.066

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.086

gMVP

0.30

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over