rs79716342

Positions:

• chr12-48917004-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033124.5(CCDC65):​c.505C>A​(p.His169Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,613,784 control chromosomes in the GnomAD database, including 2,591 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (204 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2387 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.12

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=0.0017274618).
• BP6: Variant 12-48917004-C-A is Benign according to our data. Variant chr12-48917004-C-A is described in ClinVar as [Benign]. Clinvar id is 262220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC65	NM_033124.5	c.505C>A	p.His169Asn	missense_variant	4/8	ENST00000320516.5	NP_149115.2
CCDC65	NM_001286957.2	c.76C>A	p.His26Asn	missense_variant	4/8		NP_001273886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5	c.505C>A	p.His169Asn	missense_variant	4/8	1	NM_033124.5	ENSP00000312706	P2
CCDC65	ENST00000266984.9	c.505C>A	p.His169Asn	missense_variant	4/9	5		ENSP00000266984	A2
CCDC65	ENST00000552942.5	c.301-1271C>A		intron_variant		5		ENSP00000446569
CCDC65	ENST00000547861.5	c.*336C>A		3_prime_UTR_variant, NMD_transcript_variant	4/8	2		ENSP00000447157

Frequencies

GnomAD3 genomes AF: 0.0427 AC: 6493 AN: 152104 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0612

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0412 AC: 10364 AN: 251288 Hom.: 327 AF XY: 0.0417 AC XY: 5664 AN XY: 135802

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.0994

Gnomad NFE exome AF: 0.0588

Gnomad OTH exome AF: 0.0412

GnomAD4 exome AF: 0.0520 AC: 76046 AN: 1461562 Hom.: 2387 Cov.: 32 AF XY: 0.0509 AC XY: 37009 AN XY: 727092

Gnomad4 AFR exome AF: 0.00738

Gnomad4 AMR exome AF: 0.0195

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.0980

Gnomad4 NFE exome AF: 0.0589

Gnomad4 OTH exome AF: 0.0447

GnomAD4 genome AF: 0.0426 AC: 6491 AN: 152222 Hom.: 204 Cov.: 32 AF XY: 0.0445 AC XY: 3310 AN XY: 74424

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.0330

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0612

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0501 Hom.: 368

Bravo AF: 0.0345

TwinsUK AF: 0.0585 AC: 217

ALSPAC AF: 0.0605 AC: 233

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0551 AC: 474

ExAC AF: 0.0411 AC: 4986

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0533

EpiControl AF: 0.0518

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	GeneDx	Aug 24, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	0.097
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.00099	.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.79	N;N
REVEL	Benign	0.14
Sift	Benign	0.56	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0	.;B
Vest4		0.16
MPC		0.053
ClinPred		0.0079	T
GERP RS		5.3
Varity_R		0.10
gMVP		0.090

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79716342; hg19: chr12-49310787; COSMIC: COSV56740442; COSMIC: COSV56740442;