16-89284503-G-C

Variant names:

• chr16-89284503-G-C
• rs145694621
• NM_013275.6:c.2039C>G

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.2039C>G​(p.Thr680Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,613,962 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.016 (227 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.856
• Publications: 9 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=0.0025362372).
• BP6: Variant 16-89284503-G-C is Benign according to our data. Variant chr16-89284503-G-C is described in ClinVar as Benign. ClinVar VariationId is 585403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1799/152116) while in subpopulation NFE AF = 0.0191 (1301/68006). AF 95% confidence interval is 0.0183. There are 18 homozygotes in GnomAd4. There are 849 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1799 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.2039C>G	p.Thr680Ser	missense	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.2039C>G	p.Thr680Ser	missense	Exon 10 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.2039C>G	p.Thr680Ser	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.2039C>G	p.Thr680Ser	missense	Exon 9 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.2039C>G	p.Thr680Ser	missense	Exon 10 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.2039C>G	p.Thr680Ser	missense	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1799 AN: 151998 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00623

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0114 AC: 2858 AN: 251432 AF XY: 0.0113

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.0342

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0157 AC: 22991 AN: 1461846 Hom.: 227 Cov.: 38 AF XY: 0.0155 AC XY: 11283 AN XY: 727224

African (AFR) AF: 0.00206 AC: 69 AN: 33480

American (AMR) AF: 0.00458 AC: 205 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 956 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00424 AC: 366 AN: 86256

European-Finnish (FIN) AF: 0.0119 AC: 636 AN: 53384

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0179 AC: 19941 AN: 1112004

Other (OTH) AF: 0.0133 AC: 805 AN: 60394

GnomAD4 genome AF: 0.0118 AC: 1799 AN: 152116 Hom.: 18 Cov.: 32 AF XY: 0.0114 AC XY: 849 AN XY: 74362

African (AFR) AF: 0.00284 AC: 118 AN: 41488

American (AMR) AF: 0.00622 AC: 95 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4822

European-Finnish (FIN) AF: 0.0108 AC: 114 AN: 10558

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

European-Non Finnish (NFE) AF: 0.0191 AC: 1301 AN: 68006

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.0164 Hom.: 12

Bravo AF: 0.0107

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0193 AC: 166

ExAC AF: 0.0109 AC: 1324

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	KBG syndrome (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.10
DANN	Benign	0.34
DEOGEN2	Benign	0.063	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.86
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.015
Sift	Benign	0.59	T
Sift4G	Benign	0.79	T
Polyphen		0.0030	B
Vest4		0.017
MutPred		0.11		Loss of helix (P = 0.0626)
MPC		0.39
ClinPred		0.00094	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.0017
Mutation Taster		=100/0	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: rs145694621; hg19: chr16-89350911; COSMIC: COSV99971190; COSMIC: COSV99971190;