Genetic Variant NM_001349884.2:c.719A>G (chr1-111118242-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_001349884.2(DRAM2):c.719A>G(p.Asn240Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

DRAM2
NM_001349884.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.461

Publications

1 publications found

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 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

DRAM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. 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

BP4

Computational evidence support a benign effect (MetaRNN=0.05594358).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DRAM2	NM_001349884.2	MANE Select	c.719A>G	p.Asn240Ser	missense	Exon 10 of 10	NP_001336813.1	Q6UX65
DRAM2	NM_001349881.2		c.719A>G	p.Asn240Ser	missense	Exon 10 of 10	NP_001336810.1	Q6UX65
DRAM2	NM_001349882.2		c.719A>G	p.Asn240Ser	missense	Exon 10 of 10	NP_001336811.1	Q6UX65

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DRAM2	ENST00000484310.6	TSL:1 MANE Select	c.719A>G	p.Asn240Ser	missense	Exon 10 of 10	ENSP00000503400.1	Q6UX65
DRAM2	ENST00000286692.8	TSL:1	c.719A>G	p.Asn240Ser	missense	Exon 9 of 9	ENSP00000286692.4	Q6UX65
DRAM2	ENST00000539140.6	TSL:1	c.719A>G	p.Asn240Ser	missense	Exon 9 of 9	ENSP00000437718.1	Q6UX65

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000240

AC:

AN:

250262

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460460

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33412

American (AMR)

AF:

0.0000224

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.000151

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1111216

Other (OTH)

AF:

0.0000331

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151956

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67868

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.011

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.65

M_CAP

Benign

0.0015

MetaRNN

Benign

0.056

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

PhyloP100

0.46

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.63

REVEL

Benign

0.043

Sift

Benign

0.36

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.054

MutPred

0.36

Gain of sheet (P = 0.0344)

MVP

0.34

MPC

0.10

ClinPred

0.038

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.26

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over