rs192209412

chr12-48921160-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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:3
• Conservation: PhyloP100: 0.488

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 (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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC65	NM_033124.5	c.1180-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320516.5
CCDC65	NM_001286957.2	c.751-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC65	ENST00000320516.5	c.1180-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_033124.5	P2
CCDC65	ENST00000266984.9	c.1180-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A2
CCDC65	ENST00000552942.5	c.871-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
CCDC65	ENST00000547861.5	c.*1011-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152054 Hom.: 4 Cov.: 32

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.: 8 AF XY: 0.00216 AC XY: 293 AN XY: 135812

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.: 10 Cov.: 44 AF XY: 0.000512 AC XY: 372 AN XY: 726644

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.: 4 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74392

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.: 0

Bravo AF: 0.00204

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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	Sep 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:1

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

Other links and lift over

dbSNP: rs192209412; hg19: chr12-49314943;