chr16-89268502-G-T

Variant names:

• chr16-89268502-G-T
• rs546081499
• NM_013275.6:c.7968C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013275.6(ANKRD11):​c.7968C>A​(p.Asp2656Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 144,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D2656D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.651
• Publications: 1 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: Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
• congenital heart defects, multiple types

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000268218 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23276252).

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.7968C>A	p.Asp2656Glu	missense	Exon 13 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.7968C>A	p.Asp2656Glu	missense	Exon 14 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.7968C>A	p.Asp2656Glu	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.7968C>A	p.Asp2656Glu	missense	Exon 13 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.7968C>A	p.Asp2656Glu	missense	Exon 14 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.7968C>A	p.Asp2656Glu	missense	Exon 13 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.00000693 AC: 1 AN: 144392 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1236016 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 614892

African (AFR) AF: 0.00 AC: 0 AN: 28458

American (AMR) AF: 0.00 AC: 0 AN: 35414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24090

East Asian (EAS) AF: 0.00 AC: 0 AN: 34874

South Asian (SAS) AF: 0.00 AC: 0 AN: 75616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3790

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 934246

Other (OTH) AF: 0.00 AC: 0 AN: 52396

GnomAD4 genome AF: 0.00000692 AC: 1 AN: 144508 Hom.: 0 Cov.: 27 AF XY: 0.0000143 AC XY: 1 AN XY: 70102

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

African (AFR) AF: 0.0000259 AC: 1 AN: 38646

American (AMR) AF: 0.00 AC: 0 AN: 14400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 4854

South Asian (SAS) AF: 0.00 AC: 0 AN: 4270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66092

Other (OTH) AF: 0.00 AC: 0 AN: 1944

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.65
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.49		Loss of sheet (P = 0.0817)
MVP		0.53
MPC		2.9
ClinPred		0.98	D
GERP RS		-6.8
Varity_R		0.28
gMVP		0.88
Mutation Taster		=66/34	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: rs546081499; hg19: chr16-89334910;