Genetic Variant MDC1:p.Arg2031Gln (chr6-30702563-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014641.3(MDC1):c.6092G>A(p.Arg2031Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,588,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2031P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

MDC1
NM_014641.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18421441).

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.6092G>A	p.Arg2031Gln	missense	Exon 14 of 15	NP_055456.2	Q14676-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDC1	ENST00000376406.8	TSL:5 MANE Select	c.6092G>A	p.Arg2031Gln	missense	Exon 14 of 15	ENSP00000365588.3	Q14676-1
MDC1	ENST00000939654.1		c.6092G>A	p.Arg2031Gln	missense	Exon 15 of 16	ENSP00000609713.1
MDC1	ENST00000939657.1		c.5909G>A	p.Arg1970Gln	missense	Exon 13 of 14	ENSP00000609716.1

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000446

AC:

AN:

224392

AF XY:

0.0000575

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000644

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000690

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

216

AN:

1436860

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

101

AN XY:

713344

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32720

American (AMR)

AF:

0.0000487

AC:

AN:

41074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24150

East Asian (EAS)

AF:

0.00

AC:

AN:

39598

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81526

European-Finnish (FIN)

AF:

0.0000389

AC:

AN:

51388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.000173

AC:

190

AN:

1101428

Other (OTH)

AF:

0.000354

AC:

AN:

59368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000987

AC:

AN:

151976

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41352

American (AMR)

AF:

0.0000656

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000784

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000185

AC:

ExAC

AF:

0.0000169

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

0.16

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.53

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.38

MutationAssessor

Benign

1.7

PhyloP100

1.9

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.5

REVEL

Benign

0.26

Sift

Benign

0.27

Sift4G

Uncertain

0.020

Polyphen

0.50

Vest4

0.23

MVP

0.90

MPC

0.77

ClinPred

0.14

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.16

gMVP

0.13

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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