NM_013275.6:c.6067G>C

Variant names:

• chr16-89280475-C-G
• rs60520302
• NM_013275.6:c.6067G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013275.6(ANKRD11):​c.6067G>C​(p.Ala2023Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 1,602,602 control chromosomes in the GnomAD database, including 1,621 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2023S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.041 (165 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1456 hom.)
• Consequence: ANKRD11 NM_013275.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.467
• Publications: 13 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=0.0017634332).
• BP6: Variant 16-89280475-C-G is Benign according to our data. Variant chr16-89280475-C-G is described in ClinVar as Benign. ClinVar VariationId is 380368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

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.6067G>C	p.Ala2023Pro	missense	Exon 9 of 13	NP_037407.4
	ANKRD11	NM_001256182.2		c.6067G>C	p.Ala2023Pro	missense	Exon 10 of 14	NP_001243111.1	Q6UB99
	ANKRD11	NM_001256183.2		c.6067G>C	p.Ala2023Pro	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.6067G>C	p.Ala2023Pro	missense	Exon 9 of 13	ENSP00000301030.4	Q6UB99
	ANKRD11	ENST00000378330.7	TSL:1	c.6067G>C	p.Ala2023Pro	missense	Exon 10 of 14	ENSP00000367581.2	Q6UB99
	ANKRD11	ENST00000642600.2		c.6067G>C	p.Ala2023Pro	missense	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6165 AN: 152152 Hom.: 165 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.0645

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0380

Gnomad OTH AF: 0.0321

GnomAD2 exomes AF: 0.0456 AC: 9298 AN: 203938 AF XY: 0.0437

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0784

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.0415

Gnomad OTH exome AF: 0.0489

GnomAD4 exome AF: 0.0403 AC: 58437 AN: 1450332 Hom.: 1456 Cov.: 34 AF XY: 0.0391 AC XY: 28210 AN XY: 720908

African (AFR) AF: 0.0300 AC: 997 AN: 33240

American (AMR) AF: 0.0307 AC: 1339 AN: 43666

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 282 AN: 25762

East Asian (EAS) AF: 0.0665 AC: 2613 AN: 39322

South Asian (SAS) AF: 0.0117 AC: 1002 AN: 85572

European-Finnish (FIN) AF: 0.122 AC: 6220 AN: 51074

Middle Eastern (MID) AF: 0.00792 AC: 43 AN: 5426

European-Non Finnish (NFE) AF: 0.0395 AC: 43761 AN: 1106484

Other (OTH) AF: 0.0365 AC: 2180 AN: 59786

GnomAD4 genome AF: 0.0405 AC: 6168 AN: 152270 Hom.: 165 Cov.: 32 AF XY: 0.0440 AC XY: 3277 AN XY: 74450

African (AFR) AF: 0.0311 AC: 1291 AN: 41578

American (AMR) AF: 0.0265 AC: 406 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.0649 AC: 336 AN: 5180

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4826

European-Finnish (FIN) AF: 0.129 AC: 1370 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0380 AC: 2587 AN: 67996

Other (OTH) AF: 0.0317 AC: 67 AN: 2112

Alfa AF: 0.0210 Hom.: 17

Bravo AF: 0.0331

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.0180 AC: 54

ESP6500EA AF: 0.0308 AC: 203

ExAC AF: 0.0395 AC: 4582

Asia WGS AF: 0.0420 AC: 146 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.9
DANN	Benign	0.90
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.47
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.0090
Sift	Benign	0.27	T
Sift4G	Benign	0.30	T
Polyphen		0.45	B
Vest4		0.067
MPC		0.16
ClinPred		0.0016	T
GERP RS		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.093
gMVP		0.088
Mutation Taster		=98/2	polymorphism (auto)

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: rs60520302; hg19: chr16-89346883; COSMIC: COSV56354227; COSMIC: COSV56354227;