1-111118254-C-T

Position:

chr1-111118254-C-T

Variant summary

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

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. 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00100

Variant links:

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 links:

DRAM2 (HGNC:):

DRAM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRAM2	NM_001349884.2 linkuse as main transcript	c.707G>A	p.Arg236Gln	missense_variant	10/10	ENST00000484310.6	NP_001336813.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRAM2	ENST00000484310.6 linkuse as main transcript	c.707G>A	p.Arg236Gln	missense_variant	10/10	1	NM_001349884.2	ENSP00000503400.1		Q6UX65

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151828

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248322

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134206

show subpopulations

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 SAS 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:

AN:

1458472

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725428

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000585

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151828

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 236 of the DRAM2 protein (p.Arg236Gln). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DRAM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1003613). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.055

Sift

Benign

0.086

T;T

Sift4G

Benign

0.11

T;T

Polyphen

1.0

D;D

Vest4

0.14

MutPred

0.48

Gain of methylation at K232 (P = 0.0611);Gain of methylation at K232 (P = 0.0611);

MVP

0.39

MPC

0.16

ClinPred

0.42

GERP RS

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.59

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over