10-132834775-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001200049.3(CFAP46):​c.6745G>C​(p.Glu2249Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFAP46 NM_001200049.3 missense, splice_region
• Scores: Splicing: ADA: 0.7276
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07889235).

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>C	p.Glu2249Gln	missense 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>C	p.Glu2249Gln	missense splice_region	Exon 48 of 58	ENSP00000357575.4	Q8IYW2-1
	CFAP46	ENST00000639072.2	TSL:5	c.6745G>C	p.Glu2249Gln	missense splice_region	Exon 48 of 59	ENSP00000491877.2	A0A1W2PQB9
	CFAP46	ENST00000448925.1	TSL:3	c.49G>C	p.Glu17Gln	missense splice_region	Exon 2 of 5	ENSP00000417039.1	H0Y845

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000814 AC: 2 AN: 245662 AF XY: 0.0000150

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: 0.00000206 AC: 3 AN: 1457168 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 724208

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5396

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109322

Other (OTH) AF: 0.00 AC: 0 AN: 60106

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.9
DANN	Benign	0.97
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.23
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.023
Sift	Benign	0.30	T
Sift4G	Benign	0.41	T
Vest4		0.098
MVP		0.014
MPC		0.22
ClinPred		0.080	T
GERP RS		-1.6
Varity_R		0.11
gMVP		0.13
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.19		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;