rs1380765057

Variant names:

• chr6-89612311-C-T
• rs1380765057
• NM_001242809.2:c.457C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001242809.2(ANKRD6):​c.457C>T​(p.His153Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ANKRD6 NM_001242809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD6	NM_001242809.2	c.457C>T	p.His153Tyr	missense_variant	Exon 6 of 16	ENST00000339746.9	NP_001229738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD6	ENST00000339746.9	c.457C>T	p.His153Tyr	missense_variant	Exon 6 of 16	1	NM_001242809.2	ENSP00000345767.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000562 AC: 1 AN: 177988 Hom.: 0 AF XY: 0.0000106 AC XY: 1 AN XY: 94744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000135

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1413746 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.457C>T (p.H153Y) alteration is located in exon 6 (coding exon 5) of the ANKRD6 gene. This alteration results from a C to T substitution at nucleotide position 457, causing the histidine (H) at amino acid position 153 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	.;T;.;T;T;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.4	L;L;L;.;L;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.045	D;D;D;T;D;T;D
Polyphen		1.0	D;D;.;.;D;.;.
Vest4		0.88
MutPred		0.70		Loss of disorder (P = 0.0319);Loss of disorder (P = 0.0319);Loss of disorder (P = 0.0319);Loss of disorder (P = 0.0319);Loss of disorder (P = 0.0319);Loss of disorder (P = 0.0319);.;
MVP		0.84
MPC		0.36
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.47
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs1380765057; hg19: chr6-90322030;