12-48921211-A-T

Position:

• chr12-48921211-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000320516.5(CCDC65):​c.1223A>T​(p.Tyr408Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y408C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: CCDC65 ENST00000320516.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC65	NM_033124.5	c.1223A>T	p.Tyr408Phe	missense_variant	8/8	ENST00000320516.5	NP_149115.2
CCDC65	NM_001286957.2	c.794A>T	p.Tyr265Phe	missense_variant	8/8		NP_001273886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5	c.1223A>T	p.Tyr408Phe	missense_variant	8/8	1	NM_033124.5	ENSP00000312706	P2
CCDC65	ENST00000266984.9	c.1223A>T	p.Tyr408Phe	missense_variant	8/9	5		ENSP00000266984	A2
CCDC65	ENST00000552942.5	c.914A>T	p.Tyr305Phe	missense_variant	6/6	5		ENSP00000446569
CCDC65	ENST00000547861.5	c.*1054A>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	2		ENSP00000447157

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152000 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome Cov.: 49

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152000 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74214

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

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: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	.;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.0057	T
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	2.6e-18	P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.7	D;N;D
REVEL	Benign	0.14
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.86	.;.;P
Vest4		0.20
MutPred		0.54		Gain of methylation at K406 (P = 0.0899);.;Gain of methylation at K406 (P = 0.0899);
MVP		0.014
MPC		0.055
ClinPred		0.84	D
GERP RS		4.5
Varity_R		0.21
gMVP		0.46

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: rs4760600; hg19: chr12-49314994;