rs1064796264

Variant names:

• chr16-89268543-C-T
• rs1064796264
• NM_013275.6:c.7927G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013275.6(ANKRD11):​c.7927G>A​(p.Glu2643Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E2643D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84
• 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: Ambry Genetics, G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000268218 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013275.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD11	NM_013275.6	MANE Select	c.7927G>A	p.Glu2643Lys	missense	Exon 13 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.7927G>A	p.Glu2643Lys	missense	Exon 14 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.7927G>A	p.Glu2643Lys	missense	Exon 13 of 13	NP_001243112.1	Q6UB99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD11	ENST00000301030.10	TSL:5 MANE Select	c.7927G>A	p.Glu2643Lys	missense	Exon 13 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.7927G>A	p.Glu2643Lys	missense	Exon 14 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.7927G>A	p.Glu2643Lys	missense	Exon 13 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.46e-7 AC: 1 AN: 1340614 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 661948

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30632

American (AMR) AF: 0.00 AC: 0 AN: 35610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24800

East Asian (EAS) AF: 0.00 AC: 0 AN: 35622

South Asian (SAS) AF: 0.00 AC: 0 AN: 78258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4152

European-Non Finnish (NFE) AF: 9.74e-7 AC: 1 AN: 1027026

Other (OTH) AF: 0.00 AC: 0 AN: 55874

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.76
MPC		3.2
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.31
gMVP		0.95
Mutation Taster		=42/58	disease causing

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: rs1064796264; hg19: chr16-89334951; COSMIC: COSV108109414;