6-89627583-A-C

Position:

• chr6-89627583-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001242809.2(ANKRD6):​c.1372A>C​(p.Met458Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,612,802 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (45 hom.)
• Consequence: ANKRD6 NM_001242809.2 missense, splice_region
• Scores: Splicing: ADA: 0.005898
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.36

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)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023727417).
• BP6: Variant 6-89627583-A-C is Benign according to our data. Variant chr6-89627583-A-C is described in ClinVar as [Benign]. Clinvar id is 709411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2029/152248) while in subpopulation AFR AF= 0.0468 (1945/41542). AF 95% confidence interval is 0.0451. There are 49 homozygotes in gnomad4. There are 927 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD6	NM_001242809.2	c.1372A>C	p.Met458Leu	missense_variant, splice_region_variant	14/16	ENST00000339746.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD6	ENST00000339746.9	c.1372A>C	p.Met458Leu	missense_variant, splice_region_variant	14/16	1	NM_001242809.2	A1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2016 AN: 152130 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00348 AC: 868 AN: 249166 Hom.: 25 AF XY: 0.00272 AC XY: 368 AN XY: 135190

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00142 AC: 2068 AN: 1460554 Hom.: 45 Cov.: 30 AF XY: 0.00126 AC XY: 916 AN XY: 726624

Gnomad4 AFR exome AF: 0.0501

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.0133 AC: 2029 AN: 152248 Hom.: 49 Cov.: 32 AF XY: 0.0125 AC XY: 927 AN XY: 74442

Gnomad4 AFR AF: 0.0468

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00237 Hom.: 13

Bravo AF: 0.0150

ESP6500AA AF: 0.0427 AC: 175

ESP6500EA AF: 0.000358 AC: 3

ExAC AF: 0.00420 AC: 508

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.68
DEOGEN2	Benign	0.0019	.;T;.;T;T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.78	T;.;T;T;T;T;T
MetaRNN	Benign	0.0024	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.68	.;N;N;N;.;.;.
MutationTaster	Benign	0.70	D;D;D;D;N;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.14	N;N;N;N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.51	T;T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.;.
Vest4		0.29
MutPred		0.30		.;Loss of ubiquitination at K453 (P = 0.0546);Loss of ubiquitination at K453 (P = 0.0546);Loss of ubiquitination at K453 (P = 0.0546);.;.;.;
MVP		0.65
MPC		0.049
ClinPred		0.0031	T
GERP RS		-0.61
Varity_R		0.052
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0059
dbscSNV1_RF	Benign	0.23
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

Publications

LitVar

Other links and lift over

dbSNP: rs61736690; hg19: chr6-90337302;