2-219005519-A-G

Variant names:

• chr2-219005519-A-G
• rs115409821
• NM_194302.4:c.4966T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194302.4(CFAP65):​c.4966T>C​(p.Ser1656Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000701 in 1,612,990 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: CFAP65 NM_194302.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.340
• Publications: 0 publications found

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]

CFAP65 Gene-Disease associations (from GenCC):

• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spermatogenic failure 40

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000224090 (HGNC:58353):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034730434).
• BP6: Variant 2-219005519-A-G is Benign according to our data. Variant chr2-219005519-A-G is described in ClinVar as Benign. ClinVar VariationId is 775819.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 = 0.00382 (580/151958) while in subpopulation AFR AF = 0.0134 (554/41428). AF 95% confidence interval is 0.0125. There are 5 homozygotes in GnomAd4. There are 277 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194302.4. 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
	CFAP65	NM_194302.4	MANE Select	c.4966T>C	p.Ser1656Pro	missense	Exon 32 of 35	NP_919278.2	Q6ZU64-1
	CFAP65-AS1	NR_046086.1		n.86+3219A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP65	ENST00000341552.10	TSL:5 MANE Select	c.4966T>C	p.Ser1656Pro	missense	Exon 32 of 35	ENSP00000340776.5	Q6ZU64-1
	CFAP65	ENST00000453220.5	TSL:5	c.4966T>C	p.Ser1656Pro	missense	Exon 30 of 33	ENSP00000409117.1	Q6ZU64-1
	ENSG00000224090	ENST00000441450.1	TSL:2	n.86+3219A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 578 AN: 151840 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.000969 AC: 243 AN: 250722 AF XY: 0.000722

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000549

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: 0.000164

GnomAD4 exome AF: 0.000376 AC: 550 AN: 1461032 Hom.: 2 Cov.: 31 AF XY: 0.000330 AC XY: 240 AN XY: 726798

African (AFR) AF: 0.0140 AC: 470 AN: 33458

American (AMR) AF: 0.000581 AC: 26 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.000383 AC: 2 AN: 5224

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111974

Other (OTH) AF: 0.000746 AC: 45 AN: 60330

GnomAD4 genome AF: 0.00382 AC: 580 AN: 151958 Hom.: 5 Cov.: 31 AF XY: 0.00373 AC XY: 277 AN XY: 74268

African (AFR) AF: 0.0134 AC: 554 AN: 41428

American (AMR) AF: 0.00137 AC: 21 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67950

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00143 Hom.: 3

Bravo AF: 0.00430

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.76
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.34
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.017
Sift	Benign	0.31	T
Sift4G	Benign	0.26	T
Polyphen		0.0040	B
Vest4		0.20
MVP		0.19
MPC		0.095
ClinPred		0.012	T
GERP RS		1.4
Varity_R		0.19
gMVP		0.21
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115409821; hg19: chr2-219870241;