chr6-30703467-C-T

Variant names:

• chr6-30703467-C-T
• rs376836775
• NM_014641.3:c.5633G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014641.3(MDC1):​c.5633G>A​(p.Ser1878Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,970 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (5 hom.)
• Consequence: MDC1 NM_014641.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.197
• Publications: 0 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]

MDC1-AS1 (HGNC:39764): (MDC1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00881964).
• BP6: Variant 6-30703467-C-T is Benign according to our data. Variant chr6-30703467-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2360726.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.5633G>A	p.Ser1878Asn	missense	Exon 11 of 15	NP_055456.2	Q14676-1
	MDC1-AS1	NR_133647.1		n.127+274C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDC1	ENST00000376406.8	TSL:5 MANE Select	c.5633G>A	p.Ser1878Asn	missense	Exon 11 of 15	ENSP00000365588.3	Q14676-1
	MDC1	ENST00000939654.1		c.5633G>A	p.Ser1878Asn	missense	Exon 12 of 16	ENSP00000609713.1
	MDC1	ENST00000939657.1		c.5633G>A	p.Ser1878Asn	missense	Exon 11 of 14	ENSP00000609716.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000237 AC: 59 AN: 249468 AF XY: 0.000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1461706 Hom.: 5 Cov.: 33 AF XY: 0.000153 AC XY: 111 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000856 AC: 34 AN: 39700

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112012

Other (OTH) AF: 0.00222 AC: 134 AN: 60392

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152264 Hom.: 3 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.000262 AC: 4 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.2
DANN	Benign	0.90
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.20
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.026
Sift	Benign	0.22	T
Sift4G	Uncertain	0.048	D
Polyphen		0.0	B
Vest4		0.070
MutPred		0.15		Loss of phosphorylation at S1878 (P = 0.0054)
MVP		0.24
MPC		0.18
ClinPred		0.019	T
GERP RS		-1.2
Varity_R		0.015
gMVP		0.25
Mutation Taster		=96/4	polymorphism

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: rs376836775; hg19: chr6-30671244;