6-30704252-C-T

Position:

• chr6-30704252-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014641.3(MDC1):​c.4931G>A​(p.Arg1644Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDC1 NM_014641.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0850

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069489986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDC1	NM_014641.3	c.4931G>A	p.Arg1644Lys	missense_variant	10/15	ENST00000376406.8	NP_055456.2
MDC1-AS1	NR_133647.1	n.127+1059C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDC1	ENST00000376406.8	c.4931G>A	p.Arg1644Lys	missense_variant	10/15	5	NM_014641.3	ENSP00000365588	P1
MDC1-AS1	ENST00000442150.1	n.127+1059C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2024

The c.4931G>A (p.R1644K) alteration is located in exon 10 (coding exon 9) of the MDC1 gene. This alteration results from a G to A substitution at nucleotide position 4931, causing the arginine (R) at amino acid position 1644 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.2
DANN	Benign	0.94
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.046
Sift	Benign	0.20	T
Sift4G	Benign	0.54	T
Polyphen		0.091	B
Vest4		0.060
MutPred		0.28		Gain of methylation at R1644 (P = 0.0158);
MVP		0.49
MPC		0.66
ClinPred		0.23	T
GERP RS		0.72
Varity_R		0.024
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-30672029;