rs2273238

Positions:

• chr6-89616641-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001242809.2(ANKRD6):​c.698C>T​(p.Thr233Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 1,613,750 control chromosomes in the GnomAD database, including 9,146 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (2408 hom., cov: 33)
  • Exomes 𝑓: 0.066 (6738 hom.)
• Consequence: ANKRD6 NM_001242809.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41

Genes affected

ANKRD6 (HGNC:17280): (ankyrin repeat domain 6) Predicted to be involved in negative regulation of canonical Wnt signaling pathway and positive regulation of JNK cascade. Predicted to act upstream of or within positive regulation of Wnt signaling pathway, planar cell polarity pathway. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

LYRM2 (HGNC:25229): (LYR motif containing 2)

LOC124901359 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060423315).
• BP6: Variant 6-89616641-C-T is Benign according to our data. Variant chr6-89616641-C-T is described in ClinVar as [Benign]. Clinvar id is 3060427.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD6	NM_001242809.2	c.698C>T	p.Thr233Met	missense_variant	8/16	ENST00000339746.9
LOC124901359	XR_007059673.1	n.205+5080G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD6	ENST00000339746.9	c.698C>T	p.Thr233Met	missense_variant	8/16	1	NM_001242809.2	A1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20837 AN: 152136 Hom.: 2401 Cov.: 33

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.0952

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.0595

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.115 AC: 28717 AN: 249234 Hom.: 2772 AF XY: 0.110 AC XY: 14913 AN XY: 135208

Gnomad AFR exome AF: 0.296

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.0885

Gnomad EAS exome AF: 0.248

Gnomad SAS exome AF: 0.184

Gnomad FIN exome AF: 0.0623

Gnomad NFE exome AF: 0.0394

Gnomad OTH exome AF: 0.0891

GnomAD4 exome AF: 0.0658 AC: 96227 AN: 1461496 Hom.: 6738 Cov.: 31 AF XY: 0.0683 AC XY: 49631 AN XY: 727010

Gnomad4 AFR exome AF: 0.302

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.0883

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.0595

Gnomad4 NFE exome AF: 0.0363

Gnomad4 OTH exome AF: 0.0878

GnomAD4 genome AF: 0.137 AC: 20876 AN: 152254 Hom.: 2408 Cov.: 33 AF XY: 0.140 AC XY: 10418 AN XY: 74452

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.0952

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.0595

Gnomad4 NFE AF: 0.0399

Gnomad4 OTH AF: 0.122

Alfa AF: 0.0654 Hom.: 1640

Bravo AF: 0.148

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0319 AC: 123

ESP6500AA AF: 0.264 AC: 1063

ESP6500EA AF: 0.0389 AC: 326

ExAC AF: 0.114 AC: 13780

Asia WGS AF: 0.234 AC: 810 AN: 3478

EpiCase AF: 0.0427

EpiControl AF: 0.0394

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ANKRD6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.76	T;.;T;T;T;T
MetaRNN	Benign	0.0060	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.46	N;N;N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.11	T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.72	P;P;.;P;.;.
Vest4		0.17
MPC		0.11
ClinPred		0.016	T
GERP RS		1.6
Varity_R		0.016
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2273238; hg19: chr6-90326360; COSMIC: COSV60228845; COSMIC: COSV60228845;