Genetic Variant CFAP46:p.Trp2596Arg (chr10-132808783-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001200049.3(CFAP46):c.7786T>C(p.Trp2596Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CFAP46
NM_001200049.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.25

Publications

0 publications found

Variant links:

Genes affected

CFAP46 (HGNC:25247): (cilia and flagella associated protein 46) Predicted to be involved in axoneme assembly. Predicted to be located in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

CFAP46 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.108076125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP46	NM_001200049.3 link	c.7786T>C	p.Trp2596Arg	missense_variant	Exon 58 of 58	ENST00000368586.10	NP_001186978.2	Q8IYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP46	ENST00000368586.10 link	c.7786T>C	p.Trp2596Arg	missense_variant	Exon 58 of 58	5	NM_001200049.3	ENSP00000357575.4		Q8IYW2-1
CFAP46	ENST00000639072.2 link	c.*9T>C		3_prime_UTR_variant	Exon 59 of 59	5		ENSP00000491877.2		A0A1W2PQB9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000461

AC:

AN:

216924

AF XY:

0.00000849

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1446744

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

718260

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33250

American (AMR)

AF:

0.00

AC:

AN:

42228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25806

East Asian (EAS)

AF:

0.00

AC:

AN:

39078

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105206

Other (OTH)

AF:

0.00

AC:

AN:

59856

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2722T>C (p.W908R) alteration is located in exon 23 (coding exon 23) of the CFAP46 gene. This alteration results from a T to C substitution at nucleotide position 2722, causing the tryptophan (W) at amino acid position 908 to be replaced by an arginine (R). 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

0.23

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.015

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.23

M_CAP

Benign

0.012

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.99

PhyloP100

-1.2

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.70

REVEL

Benign

0.061

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.22

MVP

0.040

MPC

0.58

ClinPred

0.22

GERP RS

-1.3

Varity_R

0.20

gMVP

0.42

Mutation Taster

=100/0

polymorphism

(source)

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

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chr10-132808783-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over