6-30703452-C-T

Position:

• chr6-30703452-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (27 hom., cov: 32)
  • Exomes 𝑓: 0.022 (418 hom.)
• Consequence: MDC1 NM_014641.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.523

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 -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDC1	NM_014641.3	c.5648G>A	p.Arg1883Gln	missense_variant	11/15	ENST00000376406.8	NP_055456.2
MDC1-AS1	NR_133647.1	n.127+259C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDC1	ENST00000376406.8	c.5648G>A	p.Arg1883Gln	missense_variant	11/15	5	NM_014641.3	ENSP00000365588	P1
MDC1-AS1	ENST00000442150.1	n.127+259C>T		intron_variant, non_coding_transcript_variant		3
MDC1	ENST00000489540.1	n.630G>A		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2514 AN: 152118 Hom.: 27 Cov.: 32

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

GnomAD3 exomes AF: 0.0173 AC: 4296 AN: 248952 Hom.: 59 AF XY: 0.0181 AC XY: 2449 AN XY: 134968

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 SAS exome AF: 0.0139

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.: 33 AF XY: 0.0218 AC XY: 15844 AN XY: 727174

Gnomad4 AFR exome AF: 0.00442

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.000730

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.0194

Gnomad4 NFE exome AF: 0.0242

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0165 AC: 2513 AN: 152236 Hom.: 27 Cov.: 32 AF XY: 0.0164 AC XY: 1218 AN XY: 74428

Gnomad4 AFR AF: 0.00477

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.0250

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0224 Hom.: 71

Bravo AF: 0.0168

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00496 AC: 15

ESP6500EA AF: 0.0196 AC: 106

ExAC AF: 0.0178 AC: 2161

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0252

EpiControl AF: 0.0261

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

MDC1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.042
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.16	N
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.059
MPC		0.29
ClinPred		0.066	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.30

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: rs28994875; hg19: chr6-30671229;