Genetic Variant ARK2C:p.Leu9Leu (chr18-46334301-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_ModerateBP6_ModerateBP7

The NM_152470.3(ARK2C):c.27C>A(p.Leu9Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000758 in 1,583,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

ARK2C
NM_152470.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.349

Publications

2 publications found

Variant links:

Genes affected

ARK2C (HGNC:31696): (arkadia (RNF111) C-terminal like ring finger ubiquitin ligase 2C) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in motor neuron axon guidance and positive regulation of BMP signaling pathway. Predicted to act upstream of or within several processes, including forelimb morphogenesis; multicellular organism aging; and nervous system development. Predicted to be part of protein-containing complex. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ARK2C links:

ENSG00000299713 (HGNC:):

ENSG00000299713 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 18-46334301-C-A is Benign according to our data. Variant chr18-46334301-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3785134.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.349 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152470.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARK2C	NM_152470.3	MANE Select	c.27C>A	p.Leu9Leu	synonymous	Exon 1 of 8	NP_689683.2	Q6ZSG1-1
ARK2C	NM_001256758.1		c.-126C>A		5_prime_UTR	Exon 1 of 6	NP_001243687.1	Q6ZSG1-2
ARK2C	NR_046357.2		n.284C>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARK2C	ENST00000269439.12	TSL:2 MANE Select	c.27C>A	p.Leu9Leu	synonymous	Exon 1 of 8	ENSP00000269439.6	Q6ZSG1-1
ARK2C	ENST00000956349.1		c.27C>A	p.Leu9Leu	synonymous	Exon 1 of 7	ENSP00000626408.1
ARK2C	ENST00000588679.1	TSL:6	c.27C>A	p.Leu9Leu	synonymous	Exon 1 of 1	ENSP00000467609.1	K7EPZ9

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151492

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000183

AC:

AN:

218806

AF XY:

0.00000832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000639

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000994

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000699

AC:

AN:

1431554

Hom.:

Cov.:

AF XY:

0.00000702

AC XY:

AN XY:

712426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29840

American (AMR)

AF:

0.00

AC:

AN:

41998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25142

East Asian (EAS)

AF:

0.00

AC:

AN:

36276

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5306

European-Non Finnish (NFE)

AF:

0.00000726

AC:

AN:

1101182

Other (OTH)

AF:

0.0000170

AC:

AN:

58974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151588

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74078

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41480

American (AMR)

AF:

0.0000656

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67846

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.35

PromoterAI

-0.080

Neutral

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over