Variant 12-48998604-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The ENST00000421952.3(DDN):c.272T>C(p.Leu91Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000056 in 1,429,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L91Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

DDN
ENST00000421952.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.36

Variant links:

Genes affected

DDN (HGNC:24458): (dendrin) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Located in cell projection and cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DDN links:

DDN-AS1 (HGNC:53464): (DDN and PRKAG1 antisense RNA 1)

DDN-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DDN	NM_015086.2 linkuse as main transcript	c.272T>C	p.Leu91Pro	missense_variant	2/2	ENST00000421952.3	NP_055901.2
DDN-AS1	NR_147178.1 linkuse as main transcript	n.258A>G		non_coding_transcript_exon_variant	1/3
DDN-AS1	NR_147179.1 linkuse as main transcript	n.258A>G		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDN	ENST00000421952.3 linkuse as main transcript	c.272T>C	p.Leu91Pro	missense_variant	2/2	1	NM_015086.2	ENSP00000390590	P1
DDN-AS1	ENST00000552933.2 linkuse as main transcript	n.238A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000560

AC:

AN:

1429144

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

711106

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:

0.00000725

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

Nov 17, 2022

The c.272T>C (p.L91P) alteration is located in exon 2 (coding exon 2) of the DDN gene. This alteration results from a T to C substitution at nucleotide position 272, causing the leucine (L) at amino acid position 91 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

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.72

MutPred

0.30

Loss of helix (P = 0.0041);

MVP

0.59

MPC

2.1

ClinPred

0.98

GERP RS

2.4

Varity_R

0.80

gMVP

0.30

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

No publications associated with this variant yet.

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