Variant chr14-69230552-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001193360.2(EXD2):c.671T>C(p.Leu224Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

EXD2
NM_001193360.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.773

Variant links:

Genes affected

EXD2 (HGNC:20217): (exonuclease 3'-5' domain containing 2) Enables 3'-5' exonuclease activity; metal ion binding activity; and protein homodimerization activity. Involved in nucleic acid metabolic process. Located in intermediate filament cytoskeleton; mitochondrial outer membrane; and site of DNA damage. [provided by Alliance of Genome Resources, Apr 2022]

EXD2 links:

GALNT16-AS1 (HGNC:55435): (GALNT16 and EXD2 antisense RNA 1)

GALNT16-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2759447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXD2	NM_001193360.2 link	c.671T>C	p.Leu224Pro	missense_variant	5/10	ENST00000685843.1	NP_001180289.1	Q9NVH0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXD2	ENST00000685843.1 link	c.671T>C	p.Leu224Pro	missense_variant	5/10		NM_001193360.2	ENSP00000510642.1		Q9NVH0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251350

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1459644

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2024

The c.671T>C (p.L224P) alteration is located in exon 5 (coding exon 3) of the EXD2 gene. This alteration results from a T to C substitution at nucleotide position 671, causing the leucine (L) at amino acid position 224 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.011

T;.;.;.;T;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.83

.;.;.;.;T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.28

T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;.;.;.;L;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.40

N;N;N;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.29

T;T;T;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T;T;T

Vest4

0.40

MutPred

0.75

.;Gain of catalytic residue at F102 (P = 0.001);Gain of catalytic residue at F102 (P = 0.001);Gain of catalytic residue at F102 (P = 0.001);.;Gain of catalytic residue at F102 (P = 0.001);Gain of catalytic residue at F102 (P = 0.001);

MVP

0.55

MPC

0.36

ClinPred

0.15

GERP RS

1.3

Varity_R

0.18

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

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