Genetic Variant POTED:p.Glu138Lys (chr21-13610640-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_174981.6(POTED):c.412G>A(p.Glu138Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 11)

Consequence

POTED
NM_174981.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.557

Variant links:

Genes affected

POTED (HGNC:23822): (POTE ankyrin domain family member D) Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

POTED links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06906518).

BP6

Variant 21-13610640-G-A is Benign according to our data. Variant chr21-13610640-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2402153.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POTED	NM_174981.6 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 1 of 11	ENST00000299443.6	NP_778146.2	Q86YR6
POTED	XM_006723997.4 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 1 of 8		XP_006724060.1
POTED	XM_011529550.3 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 1 of 7		XP_011527852.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POTED	ENST00000299443.6 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 1 of 11	1	NM_174981.6	ENSP00000299443.5		Q86YR6
POTED	ENST00000620442.4 link	c.412G>A	p.Glu138Lys	missense_variant	Exon 1 of 8	1		ENSP00000484512.1		A0A087X1W7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 03, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.8

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.0051

.;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00031

LIST_S2

Benign

0.43

T;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.069

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.84

.;L

PhyloP100

0.56

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.1

.;N

REVEL

Benign

0.040

Sift

Benign

0.72

.;T

Sift4G

Benign

0.51

T;T

Polyphen

0.46

.;P

Vest4

0.062

MutPred

0.38

Gain of MoRF binding (P = 0.0081);Gain of MoRF binding (P = 0.0081);

MVP

0.082

ClinPred

0.16

GERP RS

-0.22

Varity_R

0.031

gMVP

0.31

Mutation Taster

=98/2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over