rs12356978

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001200049.3(CFAP46):​c.6745G>T​(p.Glu2249*) 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
• 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]

CFAP46 Gene-Disease associations (from GenCC):

• CFAP46-related primary ciliary dyskinesia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP46	NM_001200049.3	MANE Select	c.6745G>T	p.Glu2249*	stop_gained splice_region	Exon 48 of 58	NP_001186978.2	Q8IYW2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP46	ENST00000368586.10	TSL:5 MANE Select	c.6745G>T	p.Glu2249*	stop_gained splice_region	Exon 48 of 58	ENSP00000357575.4	Q8IYW2-1
	CFAP46	ENST00000639072.2	TSL:5	c.6745G>T	p.Glu2249*	stop_gained splice_region	Exon 48 of 59	ENSP00000491877.2	A0A1W2PQB9
	CFAP46	ENST00000448925.1	TSL:3	c.49G>T	p.Glu17*	stop_gained splice_region	Exon 2 of 5	ENSP00000417039.1	H0Y845

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.23
Vest4		0.024
GERP RS		-1.6
Mutation Taster		=131/69	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs12356978; hg19: chr10-134648279;