rs12356978

Positions:

• chr10-132834775-C-A
• chr10-132834775-C-G
• chr10-132834775-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001200049.3(CFAP46):​c.6745G>T​(p.Glu2249Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: CFAP46 NM_001200049.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9545
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.226

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP46	NM_001200049.3	c.6745G>T	p.Glu2249Ter	stop_gained, splice_region_variant	48/58	ENST00000368586.10	NP_001186978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP46	ENST00000368586.10	c.6745G>T	p.Glu2249Ter	stop_gained, splice_region_variant	48/58	5	NM_001200049.3	ENSP00000357575	A2
CFAP46	ENST00000639072.2	c.6745G>T	p.Glu2249Ter	stop_gained, splice_region_variant	48/59	5		ENSP00000491877	P3
CFAP46	ENST00000448925.1	c.52G>T	p.Glu18Ter	stop_gained, splice_region_variant	2/5	3		ENSP00000417039
CFAP46	ENST00000476633.1	n.470G>T		splice_region_variant, non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	37
DANN	Benign	0.96
Eigen	Benign	-0.016
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.043	N
MutationTaster	Benign	1.8e-10	P;P
Vest4		0.024
GERP RS		-1.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.38		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs12356978; hg19: chr10-134648279;