chr16-89305206-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_013275.6(ANKRD11):​c.226G>A​(p.Glu76Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

ANKRD11
NM_013275.6 missense, splice_region

Scores

3
9
7
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.52
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 16-89305206-C-T is Pathogenic according to our data. Variant chr16-89305206-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANKRD11NM_013275.6 linkc.226G>A p.Glu76Lys missense_variant, splice_region_variant Exon 4 of 13 ENST00000301030.10 NP_037407.4 Q6UB99
ANKRD11NM_001256182.2 linkc.226G>A p.Glu76Lys missense_variant, splice_region_variant Exon 5 of 14 NP_001243111.1 Q6UB99
ANKRD11NM_001256183.2 linkc.226G>A p.Glu76Lys missense_variant, splice_region_variant Exon 4 of 13 NP_001243112.1 Q6UB99
ANKRD11NR_045839.2 linkn.960G>A splice_region_variant, non_coding_transcript_exon_variant Exon 5 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANKRD11ENST00000301030.10 linkc.226G>A p.Glu76Lys missense_variant, splice_region_variant Exon 4 of 13 5 NM_013275.6 ENSP00000301030.4 Q6UB99

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

KBG syndrome Pathogenic:1
Feb 22, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 76 of the ANKRD11 protein (p.Glu76Lys). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KBG syndrome (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 521463). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases Pathogenic:1
Jun 10, 2019
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Uncertain
0.069
T
BayesDel_noAF
Benign
-0.14
CADD
Pathogenic
35
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T;.;T;T;.;.;.;.;.;.;.
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
.;.;D;D;D;.;.;.;D;D;D;T
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.32
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Uncertain
2.4
M;M;.;M;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-2.6
D;D;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.21
Sift
Uncertain
0.0010
D;D;.;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.0060
D;D;.;.;D;.;.;.;.;.;.;.
Polyphen
0.18
B;B;.;B;.;.;.;.;.;.;.;.
Vest4
0.73
MutPred
0.45
Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);.;Loss of helix (P = 0.0033);
MVP
0.59
MPC
2.0
ClinPred
0.96
D
GERP RS
4.8
Varity_R
0.33
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.78
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.78
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555535454; hg19: chr16-89371614; API