rs202081612

Variant names:

• chr16-89279797-G-A
• rs202081612
• NM_013275.6:c.6745C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-89279797-G-A
• chr16-89279797-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013275.6(ANKRD11):​c.6745C>T​(p.Arg2249Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,538,542 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2249G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.565
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034091175).
• BP6: Variant 16-89279797-G-A is Benign according to our data. Variant chr16-89279797-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0011 (167/152296) while in subpopulation AFR AF = 0.00385 (160/41566). AF 95% confidence interval is 0.00336. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 167 AD gene.

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.6745C>T	p.Arg2249Cys	missense	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.6745C>T	p.Arg2249Cys	missense	Exon 10 of 14	NP_001243111.1
	ANKRD11	NM_001256183.2		c.6745C>T	p.Arg2249Cys	missense	Exon 9 of 13	NP_001243112.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANKRD11	ENST00000301030.10	TSL:5 MANE Select	c.6745C>T	p.Arg2249Cys	missense	Exon 9 of 13	ENSP00000301030.4
	ANKRD11	ENST00000378330.7	TSL:1	c.6745C>T	p.Arg2249Cys	missense	Exon 10 of 14	ENSP00000367581.2
	ANKRD11	ENST00000642600.2		c.6745C>T	p.Arg2249Cys	missense	Exon 9 of 13	ENSP00000495226.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000261 AC: 35 AN: 134218 AF XY: 0.000150

Gnomad AFR exome AF: 0.00423

Gnomad AMR exome AF: 0.000164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000944

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000606

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000131 AC: 182 AN: 1386246 Hom.: 1 Cov.: 33 AF XY: 0.000111 AC XY: 76 AN XY: 684146

African (AFR) AF: 0.00390 AC: 123 AN: 31556

American (AMR) AF: 0.000168 AC: 6 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25082

East Asian (EAS) AF: 0.0000839 AC: 3 AN: 35746

South Asian (SAS) AF: 0.0000503 AC: 4 AN: 79484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37922

Middle Eastern (MID) AF: 0.00105 AC: 5 AN: 4758

European-Non Finnish (NFE) AF: 0.0000260 AC: 28 AN: 1078260

Other (OTH) AF: 0.000225 AC: 13 AN: 57748

GnomAD4 genome AF: 0.00110 AC: 167 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74470

African (AFR) AF: 0.00385 AC: 160 AN: 41566

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000568 Hom.: 0

Bravo AF: 0.00108

ESP6500AA AF: 0.00280 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 20

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	KBG syndrome (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.76	N
PhyloP100		0.56
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.028
Sift	Benign	0.051	T
Sift4G	Uncertain	0.051	T
Polyphen		0.0050	B
Vest4		0.082
MVP		0.22
MPC		0.12
ClinPred		0.021	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.032
Mutation Taster		=98/2	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: rs202081612; hg19: chr16-89346205;