Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_013275.6(ANKRD11):c.6125A>G(p.Asp2042Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000453 in 1,565,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D2042D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

ANKRD11
NM_013275.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.78

Publications

2 publications found

Variant links:

COSMIC-nc: COSV56359593

Genes affected

ANKRD11 (HGNC:21316): (ankyrin repeat domain containing 11) This locus encodes an ankryin repeat domain-containing protein. The encoded protein inhibits ligand-dependent activation of transcription. Mutations in this gene have been associated with KBG syndrome, which is characterized by macrodontia, distinctive craniofacial features, short stature, skeletal anomalies, global developmental delay, seizures and intellectual disability. Alternatively spliced transcript variants have been described. Related pseudogenes exist on chromosomes 2 and X. [provided by RefSeq, Jan 2012]

ANKRD11 Gene-Disease associations (from GenCC):

KBG syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P, Illumina, ClinGen
congenital heart defects, multiple types
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ANKRD11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017320007).

BP6

Variant 16-89280417-T-C is Benign according to our data. Variant chr16-89280417-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 589039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000526 (80/152196) while in subpopulation AMR AF = 0.00248 (38/15302). AF 95% confidence interval is 0.00186. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 80 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013275.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANKRD11	NM_013275.6	MANE Select	c.6125A>G	p.Asp2042Gly	missense	Exon 9 of 13	NP_037407.4
ANKRD11	NM_001256182.2		c.6125A>G	p.Asp2042Gly	missense	Exon 10 of 14	NP_001243111.1
ANKRD11	NM_001256183.2		c.6125A>G	p.Asp2042Gly	missense	Exon 9 of 13	NP_001243112.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANKRD11	ENST00000301030.10	TSL:5 MANE Select	c.6125A>G	p.Asp2042Gly	missense	Exon 9 of 13	ENSP00000301030.4
ANKRD11	ENST00000378330.7	TSL:1	c.6125A>G	p.Asp2042Gly	missense	Exon 10 of 14	ENSP00000367581.2
ANKRD11	ENST00000642600.2		c.6125A>G	p.Asp2042Gly	missense	Exon 9 of 13	ENSP00000495226.1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

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:

0.000500

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000256

AC:

AN:

191452

AF XY:

0.000245

show subpopulations

Gnomad AFR exome

AF:

0.0000854

Gnomad AMR exome

AF:

0.000210

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000449

Gnomad OTH exome

AF:

0.000876

GnomAD4 exome

AF:

0.000446

AC:

630

AN:

1413656

Hom.:

Cov.:

AF XY:

0.000424

AC XY:

296

AN XY:

698094

show subpopulations

African (AFR)

AF:

0.0000311

AC:

AN:

32166

American (AMR)

AF:

0.000578

AC:

AN:

39778

Ashkenazi Jewish (ASJ)

AF:

0.0000426

AC:

AN:

23456

East Asian (EAS)

AF:

0.00

AC:

AN:

38918

South Asian (SAS)

AF:

0.00

AC:

AN:

80190

European-Finnish (FIN)

AF:

0.0000622

AC:

AN:

48236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5348

European-Non Finnish (NFE)

AF:

0.000534

AC:

581

AN:

1087642

Other (OTH)

AF:

0.000363

AC:

AN:

57922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

133

177

221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000526

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41514

American (AMR)

AF:

0.00248

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000500

AC:

AN:

67968

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000396

Hom.:

Bravo

AF:

0.00108

ExAC

AF:

0.000137

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

KBG syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.70

CADD

Benign

9.9

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.082

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.42

M_CAP

Benign

0.032

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.8

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.64

REVEL

Benign

0.028

Sift

Benign

0.32

Sift4G

Benign

0.11

Polyphen

0.0

Vest4

0.036

MVP

0.16

MPC

0.11

ClinPred

0.0092

GERP RS

0.0095

Varity_R

0.050

gMVP

0.064

Mutation Taster

=90/10

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

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

rs534182728

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over