rs765482763

Variant names:

• chr1-111118254-C-T
• rs765482763
• NM_001349884.2:c.707G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-111118254-C-T
• chr1-111118254-C-A
• chr1-111118254-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_001349884.2(DRAM2):​c.707G>A​(p.Arg236Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,300 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R236R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (1 hom.)
• Consequence: DRAM2 NM_001349884.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00100
• Publications: 1 publications found

Genes affected

DRAM2 (HGNC:28769): (DNA damage regulated autophagy modulator 2) The protein encoded by this gene binds microtubule-associated protein 1 light chain 3 and is required for autophagy. Defects in this gene are a cause of retinal dystrophy. In addition, two microRNAs (microRNA 125b-1 and microRNA 144) can bind to the mRNA of this gene and produce the disease state. [provided by RefSeq, Mar 2017]

DRAM2 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 21

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a chain DNA damage-regulated autophagy modulator protein 2 (size 265) in uniprot entity DRAM2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001349884.2

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349884.2. 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
	DRAM2	NM_001349884.2	MANE Select	c.707G>A	p.Arg236Gln	missense	Exon 10 of 10	NP_001336813.1	Q6UX65
	DRAM2	NM_001349881.2		c.707G>A	p.Arg236Gln	missense	Exon 10 of 10	NP_001336810.1	Q6UX65
	DRAM2	NM_001349882.2		c.707G>A	p.Arg236Gln	missense	Exon 10 of 10	NP_001336811.1	Q6UX65

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRAM2	ENST00000484310.6	TSL:1 MANE Select	c.707G>A	p.Arg236Gln	missense	Exon 10 of 10	ENSP00000503400.1	Q6UX65
	DRAM2	ENST00000286692.8	TSL:1	c.707G>A	p.Arg236Gln	missense	Exon 9 of 9	ENSP00000286692.4	Q6UX65
	DRAM2	ENST00000539140.6	TSL:1	c.707G>A	p.Arg236Gln	missense	Exon 9 of 9	ENSP00000437718.1	Q6UX65

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151828 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248322 AF XY: 0.00

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458472 Hom.: 1 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 725428

African (AFR) AF: 0.0000601 AC: 2 AN: 33256

American (AMR) AF: 0.00 AC: 0 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.0000585 AC: 5 AN: 85510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110522

Other (OTH) AF: 0.0000166 AC: 1 AN: 60236

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151828 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74186

African (AFR) AF: 0.0000484 AC: 2 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67866

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.0010
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.055
Sift	Benign	0.086	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.14
MutPred		0.48		Gain of methylation at K232 (P = 0.0611)
MVP		0.39
MPC		0.16
ClinPred		0.42	T
GERP RS		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.59
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765482763; hg19: chr1-111660876; COSMIC: COSV105147210; COSMIC: COSV105147210;