Genetic Variant ANKRD66:c.-29C>A (chr6-46749963-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001162435.3(ANKRD66):c.-29C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,498,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

ANKRD66
NM_001162435.3 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0880

Variant links:

Genes affected

ANKRD66 (HGNC:44669): (ankyrin repeat domain 66)

ANKRD66 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027105182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANKRD66	NM_001162435.3 link	c.-29C>A		5_prime_UTR_variant	Exon 2 of 5	ENST00000565422.3	NP_001155907.3	B4E2M5
ANKRD66	XM_017010148.2 link	c.119C>A	p.Pro40His	missense_variant	Exon 2 of 5		XP_016865637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANKRD66	ENST00000565422 link	c.-29C>A		5_prime_UTR_variant	Exon 2 of 5	2	NM_001162435.3	ENSP00000454770.2		B4E2M5

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000660

AC:

AN:

151484

Hom.:

AF XY:

0.0000496

AC XY:

AN XY:

80584

show subpopulations

Gnomad AFR exome

AF:

0.00126

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1346402

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

667290

show subpopulations

Gnomad4 AFR exome

AF:

0.000987

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:

0.00000291

Gnomad4 OTH exome

AF:

0.0000355

GnomAD4 genome

AF:

0.000361

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000493

Hom.:

Bravo

AF:

0.000427

ESP6500AA

AF:

0.00217

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000126

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137C>A (p.P46H) alteration is located in exon 2 (coding exon 2) of the ANKRD66 gene. This alteration results from a C to A substitution at nucleotide position 137, causing the proline (P) at amino acid position 46 to be replaced by a histidine (H). 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

Benign

0.094

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.25

CADD

Benign

1.3

DANN

Benign

0.90

DEOGEN2

Benign

0.0089

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.23

M_CAP

Benign

0.0062

MetaRNN

Benign

0.027

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.85

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.010

Vest4

0.46

MVP

0.38

GERP RS

0.14

Varity_R

0.17

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over