2-219009087-C-T

Position:

• chr2-219009087-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194302.4(CFAP65):​c.4634G>A​(p.Arg1545Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,612,896 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (13 hom.)
• Consequence: CFAP65 NM_194302.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.78

Genes affected

CFAP65 (HGNC:25325): (cilia and flagella associated protein 65) The protein encoded by this gene has putative coiled-coil domains and may be a transmembrane protein. The chicken ortholog of this gene is involved in the Rose-comb mutation, which is a large chromosome inversion, resulting in altered comb morphology and defects in sperm motility. [provided by RefSeq, Aug 2016]

ENSG00000224090 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007706344).
• BP6: Variant 2-219009087-C-T is Benign according to our data. Variant chr2-219009087-C-T is described in ClinVar as [Benign]. Clinvar id is 775820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00822 (1252/152306) while in subpopulation AFR AF= 0.0284 (1181/41556). AF 95% confidence interval is 0.0271. There are 20 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP65	NM_194302.4	c.4634G>A	p.Arg1545Gln	missense_variant	29/35	ENST00000341552.10	NP_919278.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP65	ENST00000341552.10	c.4634G>A	p.Arg1545Gln	missense_variant	29/35	5	NM_194302.4	ENSP00000340776.5
CFAP65	ENST00000453220.5	c.4634G>A	p.Arg1545Gln	missense_variant	27/33	5		ENSP00000409117.1
ENSG00000224090	ENST00000441450.1	n.87-870C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1250 AN: 152188 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00211 AC: 528 AN: 249730 Hom.: 10 AF XY: 0.00156 AC XY: 211 AN XY: 135524

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000801 AC: 1170 AN: 1460590 Hom.: 13 Cov.: 31 AF XY: 0.000681 AC XY: 495 AN XY: 726584

Gnomad4 AFR exome AF: 0.0287

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00822 AC: 1252 AN: 152306 Hom.: 20 Cov.: 32 AF XY: 0.00788 AC XY: 587 AN XY: 74464

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00216 Hom.: 6

Bravo AF: 0.00954

ESP6500AA AF: 0.0295 AC: 130

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00275 AC: 333

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.65
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	.;T
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;D
Vest4		0.61
MVP		0.63
MPC		0.43
ClinPred		0.053	T
GERP RS		4.4
Varity_R		0.18
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs75862278; hg19: chr2-219873809; COSMIC: COSV58562731;