chr16-89280436-C-T

Variant names:

• chr16-89280436-C-T
• rs201636725
• NM_013275.6:c.6106G>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.6106G>A​(p.Asp2036Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,581,004 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (14 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.48
• 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: 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=0.0027543604).
• BP6: Variant 16-89280436-C-T is Benign according to our data. Variant chr16-89280436-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376944.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 = 0.00607 (924/152346) while in subpopulation AFR AF = 0.0216 (899/41576). AF 95% confidence interval is 0.0204. There are 11 homozygotes in GnomAd4. There are 423 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 924 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.6106G>A	p.Asp2036Asn	missense	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.6106G>A	p.Asp2036Asn	missense	Exon 10 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.6106G>A	p.Asp2036Asn	missense	Exon 9 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.6106G>A	p.Asp2036Asn	missense	Exon 9 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.6106G>A	p.Asp2036Asn	missense	Exon 10 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.6106G>A	p.Asp2036Asn	missense	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.00607 AC: 924 AN: 152228 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00155 AC: 303 AN: 195118 AF XY: 0.00123

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.000768

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: 0.00128

GnomAD4 exome AF: 0.000582 AC: 832 AN: 1428658 Hom.: 14 Cov.: 34 AF XY: 0.000501 AC XY: 354 AN XY: 707272

African (AFR) AF: 0.0221 AC: 718 AN: 32508

American (AMR) AF: 0.000798 AC: 33 AN: 41340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24520

East Asian (EAS) AF: 0.00 AC: 0 AN: 38988

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 82996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49962

Middle Eastern (MID) AF: 0.000187 AC: 1 AN: 5340

European-Non Finnish (NFE) AF: 0.00000731 AC: 8 AN: 1094398

Other (OTH) AF: 0.00121 AC: 71 AN: 58606

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152346 Hom.: 11 Cov.: 32 AF XY: 0.00568 AC XY: 423 AN XY: 74496

African (AFR) AF: 0.0216 AC: 899 AN: 41576

American (AMR) AF: 0.000718 AC: 11 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00158 Hom.: 3

Bravo AF: 0.00664

ESP6500AA AF: 0.0110 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00162 AC: 189

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.11
Sift	Uncertain	0.018	D
Sift4G	Benign	0.12	T
Polyphen		0.28	B
Vest4		0.074
MVP		0.31
MPC		0.12
ClinPred		0.015	T
GERP RS		4.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.095
gMVP		0.043
Mutation Taster		=97/3	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: rs201636725; hg19: chr16-89346844; COSMIC: COSV107368739; COSMIC: COSV107368739;