rs2253802

Variant names:

• chr6-30716909-C-T
• rs2253802
• NM_014641.3:c.-4+336G>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.-4+336G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 983,810 control chromosomes in the GnomAD database, including 966 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.043 (197 hom., cov: 32)
  • Exomes 𝑓: 0.041 (769 hom.)
• Consequence: MDC1 NM_014641.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• Publications: 5 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	NM_014641.3	MANE Select	c.-4+336G>A		intron	N/A	NP_055456.2	Q14676-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	ENST00000376406.8	TSL:5 MANE Select	c.-4+336G>A		intron	N/A	ENSP00000365588.3	Q14676-1
	MDC1	ENST00000939654.1		c.-31G>A		5_prime_UTR	Exon 2 of 16	ENSP00000609713.1
	MDC1	ENST00000939653.1		c.-31G>A		5_prime_UTR	Exon 2 of 16	ENSP00000609712.1

Frequencies

GnomAD3 genomes AF: 0.0431 AC: 6564 AN: 152140 Hom.: 197 Cov.: 32

Gnomad AFR AF: 0.0768

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0556

GnomAD4 exome AF: 0.0408 AC: 33914 AN: 831552 Hom.: 769 Cov.: 26 AF XY: 0.0403 AC XY: 15463 AN XY: 384002

African (AFR) AF: 0.0782 AC: 1229 AN: 15726

American (AMR) AF: 0.0467 AC: 46 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 124 AN: 5146

East Asian (EAS) AF: 0.00 AC: 0 AN: 3630

South Asian (SAS) AF: 0.000243 AC: 4 AN: 16458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 284

Middle Eastern (MID) AF: 0.0105 AC: 17 AN: 1618

European-Non Finnish (NFE) AF: 0.0415 AC: 31566 AN: 760466

Other (OTH) AF: 0.0341 AC: 928 AN: 27240

GnomAD4 genome AF: 0.0432 AC: 6572 AN: 152258 Hom.: 197 Cov.: 32 AF XY: 0.0416 AC XY: 3096 AN XY: 74442

African (AFR) AF: 0.0767 AC: 3187 AN: 41526

American (AMR) AF: 0.0592 AC: 905 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0323 AC: 2194 AN: 68016

Other (OTH) AF: 0.0550 AC: 116 AN: 2108

Alfa AF: 0.0348 Hom.: 257

Bravo AF: 0.0509

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.2
DANN	Benign	0.83
PhyloP100		-0.014
PromoterAI		-0.026	Neutral
Mutation Taster		=100/0	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: rs2253802; hg19: chr6-30684686;