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GeneBe

20-13995758-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_001351661.2(MACROD2):c.-6G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,376,724 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 Benign (★).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

MACROD2
NM_001351661.2 5_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.46
Variant links:
Genes affected
MACROD2 (HGNC:16126): (mono-ADP ribosylhydrolase 2) The protein encoded by this gene is a deacetylase involved in removing ADP-ribose from mono-ADP-ribosylated proteins. The encoded protein has been shown to translocate from the nucleus to the cytoplasm upon DNA damage. [provided by RefSeq, May 2017]
SEL1L2 (HGNC:15897): (SEL1L2 adaptor subunit of SYVN1 ubiquitin ligase) Predicted to contribute to ubiquitin-protein transferase activity. Predicted to be involved in ubiquitin-dependent ERAD pathway. Predicted to be integral component of membrane. Predicted to be part of Hrd1p ubiquitin ligase ERAD-L complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.37).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 20-13995758-G-A is Benign according to our data. Variant chr20-13995758-G-A is described in ClinVar as [Benign]. Clinvar id is 3038275.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MACROD2NM_001351661.2 linkuse as main transcriptc.-6G>A 5_prime_UTR_variant 1/18 ENST00000684519.1
MACROD2NM_001351663.2 linkuse as main transcriptc.-6G>A 5_prime_UTR_variant 1/18
MACROD2NM_080676.6 linkuse as main transcriptc.-6G>A 5_prime_UTR_variant 1/17

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MACROD2ENST00000684519.1 linkuse as main transcriptc.-6G>A 5_prime_UTR_variant 1/18 NM_001351661.2 P2A1Z1Q3-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00302
AC:
434
AN:
143584
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0101
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00179
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:
0.0000306
Gnomad OTH
AF:
0.00196
GnomAD3 exomes
AF:
0.000728
AC:
181
AN:
248568
Hom.:
0
AF XY:
0.000595
AC XY:
80
AN XY:
134542
show subpopulations
Gnomad AFR exome
AF:
0.00989
Gnomad AMR exome
AF:
0.000551
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:
0.0000179
Gnomad OTH exome
AF:
0.000491
GnomAD4 exome
AF:
0.000309
AC:
381
AN:
1232988
Hom.:
1
Cov.:
36
AF XY:
0.000293
AC XY:
179
AN XY:
611130
show subpopulations
Gnomad4 AFR exome
AF:
0.0110
Gnomad4 AMR exome
AF:
0.000876
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000358
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000176
Gnomad4 OTH exome
AF:
0.000708
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00303
AC:
435
AN:
143736
Hom.:
0
Cov.:
32
AF XY:
0.00299
AC XY:
209
AN XY:
69932
show subpopulations
Gnomad4 AFR
AF:
0.0101
Gnomad4 AMR
AF:
0.00178
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000306
Gnomad4 OTH
AF:
0.00194
Alfa
AF:
0.00108
Hom.:
1
Bravo
AF:
0.00337

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

MACROD2-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMay 28, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.37
Cadd
Benign
19
Dann
Benign
0.92

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

LitVar

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

Other links and lift over

dbSNP: rs200598669; hg19: chr20-13976404; API