rs146294483

chr16-89284326-G-Achr16-89284326-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.2216C>T(p.Ser739Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,613,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. S739S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.67

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=0.017974913).
• BP6: Variant 16-89284326-G-A is Benign according to our data. Variant chr16-89284326-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000283 (414/1461626) while in subpopulation NFE AF= 0.000342 (380/1111998). AF 95% confidence interval is 0.000313. There are 0 homozygotes in gnomad4_exome. There are 202 alleles in male gnomad4_exome subpopulation. Median coverage is 38. This position pass quality control queck.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.2216C>T	p.Ser739Leu	missense_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.2216C>T	p.Ser739Leu	missense_variant	10/14
ANKRD11	NM_001256183.2	c.2216C>T	p.Ser739Leu	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.2216C>T	p.Ser739Leu	missense_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000790 AC: 12 AN: 151816 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.0000883

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000200 AC: 50 AN: 250566 Hom.: 0 AF XY: 0.000288 AC XY: 39 AN XY: 135642

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 414 AN: 1461626 Hom.: 0 Cov.: 38 AF XY: 0.000278 AC XY: 202 AN XY: 727122

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000342

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 151934 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74262

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

KBG syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 16, 2020	The ANKRD11 c.2216C>T variant is classified as Likely Benign (BS4, BP1) The ANKRD11 c.2216C>T variant is a single nucleotide change in the ANKRD11 gene, which is predicted to change the amino acid serine at position 739 in the protein to leucine. This variant does not segregate with disease (BS4). (paternally inherited) Disease causing variants in ANKRD11 are predominantly truncating variants and this variant is a missense variant (BP1). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2018

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	3.4
Dann	Benign	0.81
DEOGEN2	Benign	0.087	T;T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.25	N
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.018	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N;N;.;.
REVEL	Benign	0.035
Sift	Benign	0.59	T;T;.;.
Sift4G	Benign	0.23	T;T;.;.
Polyphen		0.0050	B;B;B;.
Vest4		0.058
MVP		0.21
MPC		0.079
ClinPred		0.0082	T
GERP RS		-1.1
Varity_R		0.015
gMVP		0.00073

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: rs146294483; hg19: chr16-89350734; COSMIC: COSV56370666; COSMIC: COSV56370666;