rs144947610

Variant names:

• chr16-89305296-C-T
• rs144947610
• NM_013275.6:c.136G>A

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.136G>A​(p.Asp46Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,613,996 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (2 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.59
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03859681).
• BP6: Variant 16-89305296-C-T is Benign according to our data. Variant chr16-89305296-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585399.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 = 0.000604 (92/152298) while in subpopulation AFR AF = 0.00212 (88/41566). AF 95% confidence interval is 0.00176. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 92 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.136G>A	p.Asp46Asn	missense	Exon 4 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.136G>A	p.Asp46Asn	missense	Exon 5 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.136G>A	p.Asp46Asn	missense	Exon 4 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.136G>A	p.Asp46Asn	missense	Exon 4 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.136G>A	p.Asp46Asn	missense	Exon 5 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.136G>A	p.Asp46Asn	missense	Exon 4 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152180 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000956

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 251246 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000623 AC: 91 AN: 1461698 Hom.: 2 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727162

African (AFR) AF: 0.00194 AC: 65 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111904

Other (OTH) AF: 0.0000994 AC: 6 AN: 60384

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152298 Hom.: 1 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74460

African (AFR) AF: 0.00212 AC: 88 AN: 41566

American (AMR) AF: 0.000131 AC: 2 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000277 Hom.: 1

Bravo AF: 0.000672

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	KBG syndrome (2)
-	-	1	ANKRD11-related disorder (1)
-	-	1	Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.67
MVP		0.68
MPC		1.9
ClinPred		0.12	T
GERP RS		4.6
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.55
gMVP		0.42
Mutation Taster		=88/12	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: rs144947610; hg19: chr16-89371704; COSMIC: COSV106096627; COSMIC: COSV106096627;