Genetic Variant NM_001242809.2:c.1372A>C (chr6-89627583-A-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001242809.2(ANKRD6):c.1372A>C(p.Met458Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,612,802 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.013 ( 49 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 45 hom. )

Consequence

ANKRD6
NM_001242809.2 missense, splice_region

Scores

Splicing: ADA: 0.005898

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.36

Publications

7 publications found

Variant links:

Genes affected

ANKRD6 (HGNC:17280): (ankyrin repeat domain 6) Predicted to be involved in negative regulation of canonical Wnt signaling pathway and positive regulation of JNK cascade. Predicted to act upstream of or within positive regulation of Wnt signaling pathway, planar cell polarity pathway. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ANKRD6 links:

LYRM2 (HGNC:25229): (LYR motif containing 2)

LYRM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023727417).

BP6

Variant 6-89627583-A-C is Benign according to our data. Variant chr6-89627583-A-C is described in ClinVar as Benign. ClinVar VariationId is 709411.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2029/152248) while in subpopulation AFR AF = 0.0468 (1945/41542). AF 95% confidence interval is 0.0451. There are 49 homozygotes in GnomAd4. There are 927 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANKRD6	NM_001242809.2	MANE Select	c.1372A>C	p.Met458Leu	missense splice_region	Exon 14 of 16	NP_001229738.1
ANKRD6	NM_001242811.1		c.1372A>C	p.Met458Leu	missense splice_region	Exon 14 of 16	NP_001229740.1
ANKRD6	NM_014942.4		c.1372A>C	p.Met458Leu	missense splice_region	Exon 14 of 16	NP_055757.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANKRD6	ENST00000339746.9	TSL:1 MANE Select	c.1372A>C	p.Met458Leu	missense splice_region	Exon 14 of 16	ENSP00000345767.4
ANKRD6	ENST00000447838.6	TSL:1	c.1372A>C	p.Met458Leu	missense splice_region	Exon 14 of 16	ENSP00000396771.2
ANKRD6	ENST00000369408.9	TSL:1	c.1267A>C	p.Met423Leu	missense splice_region	Exon 13 of 15	ENSP00000358416.5

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2016

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00348

AC:

868

AN:

249166

AF XY:

0.00272

show subpopulations

Gnomad AFR exome

AF:

0.0495

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00142

AC:

2068

AN:

1460554

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

916

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.0501

AC:

1677

AN:

33444

American (AMR)

AF:

0.00244

AC:

109

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1111152

Other (OTH)

AF:

0.00368

AC:

222

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

102

205

307

410

512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0133

AC:

2029

AN:

152248

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

927

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0468

AC:

1945

AN:

41542

American (AMR)

AF:

0.00431

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68002

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

198

296

395

494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00511

Hom.:

Bravo

AF:

0.0150

ESP6500AA

AF:

0.0427

AC:

175

ESP6500EA

AF:

0.000358

AC:

ExAC

AF:

0.00420

AC:

508

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0019

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.68

PhyloP100

2.4

PrimateAI

Benign

0.42

PROVEAN

Benign

0.14

REVEL

Benign

0.039

Sift

Benign

0.51

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.29

MutPred

0.30

Loss of ubiquitination at K453 (P = 0.0546)

MVP

0.65

MPC

0.049

ClinPred

0.0031

GERP RS

-0.61

Varity_R

0.052

gMVP

0.12

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0059

dbscSNV1_RF

Benign

0.23

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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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over