16-89284698-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013275.6(ANKRD11):c.1844C>G(p.Ala615Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,834 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A615T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0070 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (13 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00300

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019230843).
• BP6: Variant 16-89284698-G-C is Benign according to our data. Variant chr16-89284698-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 585401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89284698-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00696 (1059/152176) while in subpopulation AFR AF= 0.0239 (993/41512). AF 95% confidence interval is 0.0227. There are 13 homozygotes in gnomad4. There are 508 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1055 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.1844C>G	p.Ala615Gly	missense_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.1844C>G	p.Ala615Gly	missense_variant	10/14
ANKRD11	NM_001256183.2	c.1844C>G	p.Ala615Gly	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.1844C>G	p.Ala615Gly	missense_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1055 AN: 152058 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00173 AC: 431 AN: 249500 Hom.: 6 AF XY: 0.00137 AC XY: 186 AN XY: 135456

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000672 AC: 982 AN: 1461658 Hom.: 13 Cov.: 37 AF XY: 0.000594 AC XY: 432 AN XY: 727146

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00696 AC: 1059 AN: 152176 Hom.: 13 Cov.: 32 AF XY: 0.00683 AC XY: 508 AN XY: 74394

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.00807

ESP6500AA AF: 0.0196 AC: 86

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 13, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2017	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.022
Dann	Benign	0.52
DEOGEN2	Benign	0.12	T;T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;N;.;.
REVEL	Benign	0.031
Sift	Benign	0.24	T;T;.;.
Sift4G	Benign	0.28	T;T;.;.
Polyphen		0.0	B;B;B;.
Vest4		0.078
MVP		0.26
MPC		0.085
ClinPred		0.0097	T
GERP RS		-9.2
Varity_R		0.022
gMVP		0.0085

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: rs115797011; hg19: chr16-89351106;