rs200724087

Positions:

• chr16-89280430-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_013275.6(ANKRD11):​c.6112A>G​(p.Lys2038Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000827 in 1,579,448 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2038T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (3 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 5.76

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006870091).
• BP6: Variant 16-89280430-T-C is Benign according to our data. Variant chr16-89280430-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445802.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}. Variant chr16-89280430-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000526 (80/152226) while in subpopulation SAS AF= 0.00228 (11/4828). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.6112A>G	p.Lys2038Glu	missense_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.6112A>G	p.Lys2038Glu	missense_variant	10/14
ANKRD11	NM_001256183.2	c.6112A>G	p.Lys2038Glu	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.6112A>G	p.Lys2038Glu	missense_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000626 AC: 124 AN: 198090 Hom.: 0 AF XY: 0.000799 AC XY: 88 AN XY: 110076

Gnomad AFR exome AF: 0.000265

Gnomad AMR exome AF: 0.0000683

Gnomad ASJ exome AF: 0.00307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000530

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.000859 AC: 1226 AN: 1427222 Hom.: 3 Cov.: 34 AF XY: 0.000942 AC XY: 665 AN XY: 706296

Gnomad4 AFR exome AF: 0.0000615

Gnomad4 AMR exome AF: 0.000121

Gnomad4 ASJ exome AF: 0.00280

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00219

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000842

Gnomad4 OTH exome AF: 0.000786

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74434

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000686 Hom.: 0

Bravo AF: 0.000476

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000699 AC: 5

ExAC AF: 0.000521 AC: 61

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

KBG syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2023	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ANKRD11: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2020	This variant is associated with the following publications: (PMID: 28529015) -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ANKRD11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.88	N;N;.
REVEL	Benign	0.16
Sift	Uncertain	0.0080	D;D;.
Sift4G	Benign	0.26	T;T;.
Polyphen		0.49	P;P;P
Vest4		0.45
MVP		0.49
MPC		0.17
ClinPred		0.014	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.19
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs200724087; hg19: chr16-89346838; COSMIC: COSV105186634; COSMIC: COSV105186634;