rs4760600

chr12-48921211-A-Gchr12-48921211-A-T

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.1223A>G(p.Tyr408Cys) variant causes a missense change. The variant allele was found at a frequency of 0.37 in 1,613,700 control chromosomes in the GnomAD database, including 115,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9105 hom., cov: 31)
  • Exomes 𝑓: 0.37 (106109 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.97

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=0.0031661987).
• BP6: Variant 12-48921211-A-G is Benign according to our data. Variant chr12-48921211-A-G is described in ClinVar as [Benign]. Clinvar id is 402504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC65	NM_033124.5	c.1223A>G	p.Tyr408Cys	missense_variant	8/8	ENST00000320516.5
CCDC65	NM_001286957.2	c.794A>G	p.Tyr265Cys	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC65	ENST00000320516.5	c.1223A>G	p.Tyr408Cys	missense_variant	8/8	1	NM_033124.5	P2
CCDC65	ENST00000266984.9	c.1223A>G	p.Tyr408Cys	missense_variant	8/9	5		A2
CCDC65	ENST00000552942.5	c.914A>G	p.Tyr305Cys	missense_variant	6/6	5
CCDC65	ENST00000547861.5	c.*1054A>G		3_prime_UTR_variant, NMD_transcript_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49528 AN: 151948 Hom.: 9098 Cov.: 31

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.357

GnomAD3 exomes AF: 0.382 AC: 95798 AN: 251020 Hom.: 19885 AF XY: 0.373 AC XY: 50646 AN XY: 135676

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.438

Gnomad EAS exome AF: 0.466

Gnomad SAS exome AF: 0.220

Gnomad FIN exome AF: 0.383

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.375 AC: 547957 AN: 1461636 Hom.: 106109 Cov.: 49 AF XY: 0.371 AC XY: 270029 AN XY: 727120

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.538

Gnomad4 ASJ exome AF: 0.432

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.326 AC: 49545 AN: 152064 Hom.: 9105 Cov.: 31 AF XY: 0.329 AC XY: 24482 AN XY: 74322

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.474

Gnomad4 ASJ AF: 0.435

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.221

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.359

Alfa AF: 0.381 Hom.: 29306

Bravo AF: 0.337

TwinsUK AF: 0.374 AC: 1386

ALSPAC AF: 0.375 AC: 1444

ESP6500AA AF: 0.158 AC: 695

ESP6500EA AF: 0.382 AC: 3287

ExAC AF: 0.369 AC: 44788

Asia WGS AF: 0.358 AC: 1243 AN: 3478

EpiCase AF: 0.389

EpiControl AF: 0.392

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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	2.4e-18	P;P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.26
MPC		0.36
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.62
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4760600; hg19: chr12-49314994; COSMIC: COSV56739607; COSMIC: COSV56739607;