rs2253802

Positions:

• chr6-30716909-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.-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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MDC1	NM_014641.3	c.-4+336G>A		intron_variant		ENST00000376406.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MDC1	ENST00000376406.8	c.-4+336G>A		intron_variant		5	NM_014641.3	P1
MDC1	ENST00000422266.1	c.-31G>A		5_prime_UTR_variant	1/3	3
MDC1	ENST00000416571.5	c.-4+175G>A		intron_variant		3
MDC1	ENST00000425072.5	c.-4+340G>A		intron_variant		3

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

Gnomad4 AFR exome AF: 0.0782

Gnomad4 AMR exome AF: 0.0467

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0415

Gnomad4 OTH exome AF: 0.0341

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

Gnomad4 AFR AF: 0.0767

Gnomad4 AMR AF: 0.0592

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0550

Alfa AF: 0.0348 Hom.: 42

Bravo AF: 0.0509

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.2
DANN	Benign	0.83

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: rs2253802; hg19: chr6-30684686;