10-132834775-C-T

Variant names:

• chr10-132834775-C-T
• rs12356978
• NM_001200049.3:c.6745G>A

Variant summary

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

The NM_001200049.3(CFAP46):​c.6745G>A​(p.Glu2249Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 1,609,360 control chromosomes in the GnomAD database, including 3,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.052 (279 hom., cov: 34)
  • Exomes 𝑓: 0.067 (3571 hom.)
• Consequence: CFAP46 NM_001200049.3 missense, splice_region
• Scores: Splicing: ADA: 0.009252
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.226
• Publications: 11 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=0.0035960674).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP46	NM_001200049.3	c.6745G>A	p.Glu2249Lys	missense_variant, splice_region_variant	Exon 48 of 58	ENST00000368586.10	NP_001186978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP46	ENST00000368586.10	c.6745G>A	p.Glu2249Lys	missense_variant, splice_region_variant	Exon 48 of 58	5	NM_001200049.3	ENSP00000357575.4
CFAP46	ENST00000639072.2	c.6745G>A	p.Glu2249Lys	missense_variant, splice_region_variant	Exon 48 of 59	5		ENSP00000491877.2
CFAP46	ENST00000448925.1	c.49G>A	p.Glu17Lys	missense_variant, splice_region_variant	Exon 2 of 5	3		ENSP00000417039.1
CFAP46	ENST00000476633.1	n.470G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.0520 AC: 7912 AN: 152192 Hom.: 277 Cov.: 34

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.0613

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.0998

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0742

Gnomad OTH AF: 0.0392

GnomAD2 exomes AF: 0.0580 AC: 14239 AN: 245662 AF XY: 0.0591

Gnomad AFR exome AF: 0.00961

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.0628

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.0721

Gnomad OTH exome AF: 0.0582

GnomAD4 exome AF: 0.0669 AC: 97479 AN: 1457050 Hom.: 3571 Cov.: 32 AF XY: 0.0666 AC XY: 48225 AN XY: 724132

African (AFR) AF: 0.00900 AC: 300 AN: 33342

American (AMR) AF: 0.0240 AC: 1070 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.0489 AC: 1273 AN: 26046

East Asian (EAS) AF: 0.0712 AC: 2816 AN: 39570

South Asian (SAS) AF: 0.0419 AC: 3605 AN: 86066

European-Finnish (FIN) AF: 0.104 AC: 5507 AN: 52810

Middle Eastern (MID) AF: 0.0202 AC: 109 AN: 5396

European-Non Finnish (NFE) AF: 0.0712 AC: 79014 AN: 1109224

Other (OTH) AF: 0.0630 AC: 3785 AN: 60104

GnomAD4 genome AF: 0.0520 AC: 7914 AN: 152310 Hom.: 279 Cov.: 34 AF XY: 0.0527 AC XY: 3925 AN XY: 74464

African (AFR) AF: 0.0114 AC: 475 AN: 41584

American (AMR) AF: 0.0316 AC: 484 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3472

East Asian (EAS) AF: 0.0616 AC: 318 AN: 5162

South Asian (SAS) AF: 0.0429 AC: 207 AN: 4826

European-Finnish (FIN) AF: 0.0998 AC: 1060 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0742 AC: 5046 AN: 68018

Other (OTH) AF: 0.0388 AC: 82 AN: 2112

Alfa AF: 0.0641 Hom.: 751

Bravo AF: 0.0442

TwinsUK AF: 0.0677 AC: 251

ALSPAC AF: 0.0693 AC: 267

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.0688 AC: 592

ExAC AF: 0.0586 AC: 7113

Asia WGS AF: 0.0370 AC: 128 AN: 3478

EpiCase AF: 0.0649

EpiControl AF: 0.0646

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.1
DANN	Benign	0.92
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.23
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.029
Sift	Benign	0.36	T
Sift4G	Uncertain	0.019	D
Vest4		0.050
MPC		0.18
ClinPred		0.0046	T
GERP RS		-1.6
Varity_R		0.090
gMVP		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0093
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.080		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: rs12356978; hg19: chr10-134648279; COSMIC: COSV54150987;