10-132810455-T-C

Variant names:

• chr10-132810455-T-C
• rs2254419
• NM_001200049.3:c.7618A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001200049.3(CFAP46):​c.7618A>G​(p.Ser2540Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,613,188 control chromosomes in the GnomAD database, including 397,900 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.75 (44546 hom., cov: 33)
  • Exomes 𝑓: 0.69 (353354 hom.)
• Consequence: CFAP46 NM_001200049.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.43
• Publications: 24 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0957259E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001200049.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP46	NM_001200049.3	MANE Select	c.7618A>G	p.Ser2540Gly	missense	Exon 57 of 58	NP_001186978.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP46	ENST00000368586.10	TSL:5 MANE Select	c.7618A>G	p.Ser2540Gly	missense	Exon 57 of 58	ENSP00000357575.4
	CFAP46	ENST00000639072.2	TSL:5	c.7755A>G	p.Thr2585Thr	synonymous	Exon 58 of 59	ENSP00000491877.2

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114602 AN: 152044 Hom.: 44484 Cov.: 33

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.756

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.742

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.745

Gnomad NFE AF: 0.693

Gnomad OTH AF: 0.720

GnomAD2 exomes AF: 0.680 AC: 168973 AN: 248426 AF XY: 0.687

Gnomad AFR exome AF: 0.943

Gnomad AMR exome AF: 0.412

Gnomad ASJ exome AF: 0.756

Gnomad EAS exome AF: 0.734

Gnomad FIN exome AF: 0.737

Gnomad NFE exome AF: 0.692

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.692 AC: 1011024 AN: 1461026 Hom.: 353354 Cov.: 57 AF XY: 0.693 AC XY: 503838 AN XY: 726850

African (AFR) AF: 0.946 AC: 31663 AN: 33478

American (AMR) AF: 0.425 AC: 19016 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 19767 AN: 26130

East Asian (EAS) AF: 0.733 AC: 29105 AN: 39696

South Asian (SAS) AF: 0.705 AC: 60831 AN: 86254

European-Finnish (FIN) AF: 0.736 AC: 38950 AN: 52910

Middle Eastern (MID) AF: 0.684 AC: 3945 AN: 5766

European-Non Finnish (NFE) AF: 0.688 AC: 764899 AN: 1111696

Other (OTH) AF: 0.710 AC: 42848 AN: 60376

GnomAD4 genome AF: 0.754 AC: 114712 AN: 152162 Hom.: 44546 Cov.: 33 AF XY: 0.749 AC XY: 55701 AN XY: 74372

African (AFR) AF: 0.939 AC: 39034 AN: 41550

American (AMR) AF: 0.557 AC: 8514 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 2576 AN: 3470

East Asian (EAS) AF: 0.728 AC: 3745 AN: 5146

South Asian (SAS) AF: 0.709 AC: 3417 AN: 4818

European-Finnish (FIN) AF: 0.742 AC: 7858 AN: 10590

Middle Eastern (MID) AF: 0.736 AC: 215 AN: 292

European-Non Finnish (NFE) AF: 0.693 AC: 47136 AN: 67982

Other (OTH) AF: 0.723 AC: 1529 AN: 2114

Alfa AF: 0.713 Hom.: 116982

Bravo AF: 0.749

TwinsUK AF: 0.694 AC: 2575

ALSPAC AF: 0.674 AC: 2596

ESP6500AA AF: 0.937 AC: 4128

ESP6500EA AF: 0.690 AC: 5933

ExAC AF: 0.694 AC: 84292

Asia WGS AF: 0.728 AC: 2530 AN: 3478

EpiCase AF: 0.693

EpiControl AF: 0.692

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0010
DANN	Benign	0.22
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.97	T
PhyloP100		-5.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.011
Sift	Benign	0.058	T
Sift4G	Benign	0.39	T
Vest4		0.036
MPC		0.098
ClinPred		0.0055	T
GERP RS		-6.0
Varity_R		0.036
gMVP		0.042
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2254419; hg19: chr10-134623959; COSMIC: COSV54155884;