rs534182728

chr16-89280417-T-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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.78

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=0.017320007).
• 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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD11	NM_013275.6	c.6125A>G	p.Asp2042Gly	missense_variant	9/13	ENST00000301030.10
ANKRD11	NM_001256182.2	c.6125A>G	p.Asp2042Gly	missense_variant	10/14
ANKRD11	NM_001256183.2	c.6125A>G	p.Asp2042Gly	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD11	ENST00000301030.10	c.6125A>G	p.Asp2042Gly	missense_variant	9/13	5	NM_013275.6	P1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152078 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000256 AC: 49 AN: 191452 Hom.: 0 AF XY: 0.000245 AC XY: 26 AN XY: 106046

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 SAS 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.: 0 Cov.: 34 AF XY: 0.000424 AC XY: 296 AN XY: 698094

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.000578

Gnomad4 ASJ exome AF: 0.0000426

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000622

Gnomad4 NFE exome AF: 0.000534

Gnomad4 OTH exome AF: 0.000363

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74426

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000396 Hom.: 0

Bravo AF: 0.00108

ExAC AF: 0.000137 AC: 16

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ANKRD11: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2021	This variant is associated with the following publications: (PMID: 25852444) -

KBG syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	9.9
Dann	Benign	0.75
DEOGEN2	Benign	0.082	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.34	N
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.64	N;N;.
REVEL	Benign	0.028
Sift	Benign	0.32	T;T;.
Sift4G	Benign	0.11	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.036
MVP		0.16
MPC		0.11
ClinPred		0.0092	T
GERP RS		0.0095
Varity_R		0.050
gMVP		0.064

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: rs534182728; hg19: chr16-89346825; COSMIC: COSV56359593; COSMIC: COSV56359593;