rs117927481

Positions:

• chr12-48921417-G-A

Variant summary

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

The NM_033124.5(CCDC65):​c.1429G>A​(p.Gly477Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,610,356 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (46 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.897

Genes affected

CCDC65 (HGNC:29937): (coiled-coil domain containing 65) This gene encodes a sperm tail protein that is highly expressed in adult testis, spermatocytes and spermatids. The protein plays a critical role in the assembly of the nexin-dynein regulatory complex. Mutations in this gene result in primary ciliary dyskinesia. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036070347).
• BP6: Variant 12-48921417-G-A is Benign according to our data. Variant chr12-48921417-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48921417-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00593 (902/152132) while in subpopulation NFE AF= 0.00947 (644/68008). AF 95% confidence interval is 0.00886. There are 5 homozygotes in gnomad4. There are 426 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC65	NM_033124.5	c.1429G>A	p.Gly477Ser	missense_variant	8/8	ENST00000320516.5	NP_149115.2
CCDC65	NM_001286957.2	c.1000G>A	p.Gly334Ser	missense_variant	8/8		NP_001273886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5	c.1429G>A	p.Gly477Ser	missense_variant	8/8	1	NM_033124.5	ENSP00000312706	P2
CCDC65	ENST00000266984.9	c.1429G>A	p.Gly477Ser	missense_variant, splice_region_variant	8/9	5		ENSP00000266984	A2
CCDC65	ENST00000552942.5	c.1120G>A	p.Ter374=	incomplete_terminal_codon_variant, coding_sequence_variant	6/6	5		ENSP00000446569
CCDC65	ENST00000547861.5	c.*1260G>A		3_prime_UTR_variant, NMD_transcript_variant	8/8	2		ENSP00000447157

Frequencies

GnomAD3 genomes AF: 0.00593 AC: 902 AN: 152024 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00995

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00947

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00611 AC: 1534 AN: 251102 Hom.: 8 AF XY: 0.00579 AC XY: 785 AN XY: 135678

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.00966

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00730 AC: 10649 AN: 1458224 Hom.: 46 Cov.: 36 AF XY: 0.00710 AC XY: 5141 AN XY: 724568

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.00848

Gnomad4 OTH exome AF: 0.00579

GnomAD4 genome AF: 0.00593 AC: 902 AN: 152132 Hom.: 5 Cov.: 32 AF XY: 0.00573 AC XY: 426 AN XY: 74366

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00380

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00995

Gnomad4 NFE AF: 0.00947

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00819 Hom.: 11

Bravo AF: 0.00562

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00654 AC: 794

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00942

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CCDC65: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2020	- -

Primary ciliary dyskinesia 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.81
DEOGEN2	Benign	0.0041	.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.021
Sift	Benign	0.86	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0040	.;B
Vest4		0.12
MVP		0.030
MPC		0.059
ClinPred		0.0052	T
GERP RS		1.0
Varity_R		0.034
gMVP		0.23

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: rs117927481; hg19: chr12-49315200;