16-89279872-C-T

Position:

• chr16-89279872-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013275.6(ANKRD11):​c.6670G>A​(p.Glu2224Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,422,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.440

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06493473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANKRD11	NM_013275.6	c.6670G>A	p.Glu2224Lys	missense_variant	9/13	ENST00000301030.10	NP_037407.4
ANKRD11	NM_001256182.2	c.6670G>A	p.Glu2224Lys	missense_variant	10/14		NP_001243111.1
ANKRD11	NM_001256183.2	c.6670G>A	p.Glu2224Lys	missense_variant	9/13		NP_001243112.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANKRD11	ENST00000301030.10	c.6670G>A	p.Glu2224Lys	missense_variant	9/13	5	NM_013275.6	ENSP00000301030.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181436 Hom.: 0 AF XY: 0.0000100 AC XY: 1 AN XY: 99904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000115

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1422008 Hom.: 0 Cov.: 34 AF XY: 0.00000426 AC XY: 3 AN XY: 704632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000393

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.095	T;T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.81	.;.;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.63	N;N;.
REVEL	Benign	0.018
Sift	Benign	0.091	T;T;.
Sift4G	Benign	0.75	T;T;.
Polyphen		0.085	B;B;B
Vest4		0.11
MutPred		0.17		Gain of ubiquitination at E2224 (P = 0.0025);Gain of ubiquitination at E2224 (P = 0.0025);Gain of ubiquitination at E2224 (P = 0.0025);
MVP		0.31
MPC		0.11
ClinPred		0.057	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.056

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: rs1381957912; hg19: chr16-89346280; COSMIC: COSV56376137; COSMIC: COSV56376137;