Genetic Variant AKNAD1:p.Lys835Asn (chr1-108816177-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152763.5(AKNAD1):c.2505A>C(p.Lys835Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,604,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.00010 ( 0 hom. )

Consequence

AKNAD1
NM_152763.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.673

Publications

1 publications found

Variant links:

Genes affected

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

AKNAD1 links:

ENSG00000301958 (HGNC:):

ENSG00000301958 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.1700769).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKNAD1	NM_152763.5 link	c.2505A>C	p.Lys835Asn	missense_variant	Exon 16 of 16	ENST00000370001.8	NP_689976.2	Q5T1N1-1
AKNAD1	NR_049760.2 link	n.2635A>C		non_coding_transcript_exon_variant	Exon 14 of 14
LOC105378891	XR_007066280.1 link	n.53+2535T>G		intron_variant	Intron 1 of 2
LOC105378891	XR_947687.3 link	n.53+2535T>G		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKNAD1	ENST00000370001.8 link	c.2505A>C	p.Lys835Asn	missense_variant	Exon 16 of 16	1	NM_152763.5	ENSP00000359018.3		Q5T1N1-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000411

AC:

AN:

243512

AF XY:

0.0000304

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

149

AN:

1452242

Hom.:

Cov.:

AF XY:

0.0000984

AC XY:

AN XY:

721728

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33062

American (AMR)

AF:

0.00

AC:

AN:

43036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25908

East Asian (EAS)

AF:

0.00

AC:

AN:

39386

South Asian (SAS)

AF:

0.00

AC:

AN:

83172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.000124

AC:

137

AN:

1108682

Other (OTH)

AF:

0.000200

AC:

AN:

60066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2505A>C (p.K835N) alteration is located in exon 16 (coding exon 15) of the AKNAD1 gene. This alteration results from a A to C substitution at nucleotide position 2505, causing the lysine (K) at amino acid position 835 to be replaced by an asparagine (N). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0088

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.43

M_CAP

Benign

0.0088

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

0.67

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

REVEL

Benign

0.088

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.13

MutPred

0.23

Loss of ubiquitination at K835 (P = 0.1306);

MVP

0.030

MPC

0.21

ClinPred

0.20

GERP RS

2.1

Varity_R

0.11

gMVP

0.052

Mutation Taster

=94/6

polymorphism

(source)

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

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1-108816177-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over