rs80052257

Positions:

• chr12-48921403-G-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.1415G>A​(p.Arg472His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,613,282 control chromosomes in the GnomAD database, including 313 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 0.025 (168 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (145 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.991

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]

ENSG00000272822 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019032955).
• BP6: Variant 12-48921403-G-A is Benign according to our data. Variant chr12-48921403-G-A is described in ClinVar as [Benign]. Clinvar id is 416602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC65	NM_033124.5	c.1415G>A	p.Arg472His	missense_variant	8/8	ENST00000320516.5	NP_149115.2
CCDC65	NM_001286957.2	c.986G>A	p.Arg329His	missense_variant	8/8		NP_001273886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5	c.1415G>A	p.Arg472His	missense_variant	8/8	1	NM_033124.5	ENSP00000312706.4
ENSG00000272822	ENST00000398092.4	c.385-17495C>T		intron_variant		3		ENSP00000438507.1

Frequencies

GnomAD3 genomes AF: 0.0248 AC: 3769 AN: 152000 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.0849

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0245

GnomAD3 exomes AF: 0.00639 AC: 1607 AN: 251382 Hom.: 52 AF XY: 0.00454 AC XY: 617 AN XY: 135860

Gnomad AFR exome AF: 0.0870

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00264 AC: 3854 AN: 1461164 Hom.: 145 Cov.: 36 AF XY: 0.00228 AC XY: 1655 AN XY: 726762

Gnomad4 AFR exome AF: 0.0899

Gnomad4 AMR exome AF: 0.00514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.0248 AC: 3780 AN: 152118 Hom.: 168 Cov.: 32 AF XY: 0.0229 AC XY: 1702 AN XY: 74354

Gnomad4 AFR AF: 0.0849

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.00428 Hom.: 34

Bravo AF: 0.0282

ESP6500AA AF: 0.0810 AC: 357

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00797 AC: 968

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 27 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.74
DEOGEN2	Benign	0.0050	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.073
MVP		0.055
MPC		0.059
ClinPred		0.0089	T
GERP RS		2.2
Varity_R		0.033
gMVP		0.27

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: rs80052257; hg19: chr12-49315186; COSMIC: COSV56739985; COSMIC: COSV56739985;