chr12-48914501-A-G

Position:

• chr12-48914501-A-G

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.398A>G​(p.His133Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,613,544 control chromosomes in the GnomAD database, including 115,383 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H133Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.33 (9159 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106224 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.33

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=1.7789006E-4).
• BP6: Variant 12-48914501-A-G is Benign according to our data. Variant chr12-48914501-A-G is described in ClinVar as [Benign]. Clinvar id is 402501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC65	NM_033124.5	c.398A>G	p.His133Arg	missense_variant	3/8	ENST00000320516.5
CCDC65	NM_001286957.2	c.-32A>G		5_prime_UTR_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC65	ENST00000320516.5	c.398A>G	p.His133Arg	missense_variant	3/8	1	NM_033124.5	P2
CCDC65	ENST00000266984.9	c.398A>G	p.His133Arg	missense_variant	3/9	5		A2
CCDC65	ENST00000552942.5	c.301-3774A>G		intron_variant		5
CCDC65	ENST00000547861.5	c.*229A>G		3_prime_UTR_variant, NMD_transcript_variant	3/8	2

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49763 AN: 151988 Hom.: 9150 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.435

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.361

GnomAD3 exomes AF: 0.382 AC: 96026 AN: 251288 Hom.: 19998 AF XY: 0.374 AC XY: 50766 AN XY: 135826

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.437

Gnomad EAS exome AF: 0.469

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: 548147 AN: 1461438 Hom.: 106224 Cov.: 40 AF XY: 0.372 AC XY: 270117 AN XY: 727052

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.538

Gnomad4 ASJ exome AF: 0.432

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.367

GnomAD4 genome AF: 0.327 AC: 49784 AN: 152106 Hom.: 9159 Cov.: 32 AF XY: 0.331 AC XY: 24601 AN XY: 74352

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.476

Gnomad4 ASJ AF: 0.435

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.221

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.365

Alfa AF: 0.367 Hom.: 10261

Bravo AF: 0.338

TwinsUK AF: 0.374 AC: 1386

ALSPAC AF: 0.375 AC: 1445

ESP6500AA AF: 0.161 AC: 711

ESP6500EA AF: 0.382 AC: 3288

ExAC AF: 0.370 AC: 44889

Asia WGS AF: 0.360 AC: 1250 AN: 3478

EpiCase AF: 0.389

EpiControl AF: 0.392

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.46
DEOGEN2	Benign	0.00032	.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.00018	T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.56	N;N
REVEL	Benign	0.086
Sift	Benign	0.57	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0	.;B
Vest4		0.018
MPC		0.057
ClinPred		0.0078	T
GERP RS		0.87
Varity_R		0.026
gMVP		0.031

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: rs10747556; hg19: chr12-49308284; COSMIC: COSV57194967; COSMIC: COSV57194967;