NM_013275.6:c.6919C>A

Variant names:

• chr16-89279623-G-T
• rs575642464
• NM_013275.6:c.6919C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013275.6(ANKRD11):​c.6919C>A​(p.Pro2307Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2307S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.606
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05260226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.6919C>A	p.Pro2307Thr	missense_variant	Exon 9 of 13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.6919C>A	p.Pro2307Thr	missense_variant	Exon 10 of 14		NP_001243111.1
ANKRD11	NM_001256183.2	c.6919C>A	p.Pro2307Thr	missense_variant	Exon 9 of 13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.6919C>A	p.Pro2307Thr	missense_variant	Exon 9 of 13	5	NM_013275.6	ENSP00000301030.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000179 AC: 1 AN: 55930 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000155 AC: 2 AN: 1286334 Hom.: 0 Cov.: 31 AF XY: 0.00000160 AC XY: 1 AN XY: 624718

African (AFR) AF: 0.00 AC: 0 AN: 28352

American (AMR) AF: 0.00 AC: 0 AN: 21046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19112

East Asian (EAS) AF: 0.00 AC: 0 AN: 34938

South Asian (SAS) AF: 0.0000315 AC: 2 AN: 63562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1032144

Other (OTH) AF: 0.00 AC: 0 AN: 53528

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

KBG syndrome Uncertain:1

May 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANKRD11 protein function. This variant has not been reported in the literature in individuals affected with ANKRD11-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2307 of the ANKRD11 protein (p.Pro2307Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.2
DANN	Benign	0.14
DEOGEN2	Benign	0.089	T;T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.68	.;.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N
PhyloP100		0.61
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.48	N;N;.
REVEL	Benign	0.016
Sift	Benign	0.038	D;D;.
Sift4G	Benign	0.44	T;T;.
Polyphen		0.0030	B;B;B
Vest4		0.14
MutPred		0.16		Gain of glycosylation at P2307 (P = 0.0218);Gain of glycosylation at P2307 (P = 0.0218);Gain of glycosylation at P2307 (P = 0.0218);
MVP		0.33
MPC		1.9
ClinPred		0.034	T
GERP RS		1.6
Varity_R		0.040
gMVP		0.057
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs575642464; hg19: chr16-89346031;