rs192209412

Positions:

chr12-48921160-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033124.5(CCDC65):c.1180-8A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00063 in 1,613,212 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00055 ( 10 hom. )

Consequence

CCDC65
NM_033124.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0004844

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.488

Variant links:

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]

CCDC65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-48921160-A-C is Benign according to our data. Variant chr12-48921160-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 241744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00143 (218/152172) while in subpopulation AMR AF= 0.0123 (188/15262). AF 95% confidence interval is 0.0109. There are 4 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC65	NM_033124.5 linkuse as main transcript	c.1180-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320516.5	NP_149115.2
CCDC65	NM_001286957.2 linkuse as main transcript	c.751-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001273886.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5 linkuse as main transcript	c.1180-8A>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_033124.5	ENSP00000312706	P2	Q8IXS2-1
CCDC65	ENST00000266984.9 linkuse as main transcript	c.1180-8A>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5		ENSP00000266984	A2	Q8IXS2-2
CCDC65	ENST00000552942.5 linkuse as main transcript	c.871-8A>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5		ENSP00000446569
CCDC65	ENST00000547861.5 linkuse as main transcript	c.*1011-8A>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant	2		ENSP00000447157

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

216

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00256

AC:

643

AN:

251200

Hom.:

AF XY:

0.00216

AC XY:

293

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000678

Gnomad AMR exome

AF:

0.0180

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000546

AC:

798

AN:

1461040

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

372

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.0168

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.00143

AC:

218

AN:

152172

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

118

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000556

Hom.:

Bravo

AF:

0.00204

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 27

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.6

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00048

dbscSNV1_RF

Benign

0.018

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over