11-69648088-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_053056.3(CCND1):c.669C>T(p.Phe223=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 1,613,888 control chromosomes in the GnomAD database, including 1,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (452 hom., cov: 33)
  • Exomes 𝑓: 0.033 (1368 hom.)
• Consequence: CCND1 NM_053056.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.69

Genes affected

CCND1 (HGNC:1582): (cyclin D1) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of human cancers. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 11-69648088-C-T is Benign according to our data. Variant chr11-69648088-C-T is described in ClinVar as [Benign]. Clinvar id is 1250573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.69 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCND1	NM_053056.3	c.669C>T	p.Phe223=	synonymous_variant	4/5	ENST00000227507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCND1	ENST00000227507.3	c.669C>T	p.Phe223=	synonymous_variant	4/5	1	NM_053056.3	P1
CCND1	ENST00000542367.1	n.132C>T		non_coding_transcript_exon_variant	1/2	1
CCND1	ENST00000536559.1	c.*89C>T		3_prime_UTR_variant	2/2	3
CCND1	ENST00000545484.1	n.375C>T		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9070 AN: 152184 Hom.: 445 Cov.: 33

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0453

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0994

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0280

Gnomad OTH AF: 0.0722

GnomAD3 exomes AF: 0.0393 AC: 9888 AN: 251296 Hom.: 376 AF XY: 0.0408 AC XY: 5544 AN XY: 135872

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.0103

Gnomad SAS exome AF: 0.0920

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0331 AC: 48352 AN: 1461586 Hom.: 1368 Cov.: 31 AF XY: 0.0346 AC XY: 25167 AN XY: 727116

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.0258

Gnomad4 ASJ exome AF: 0.0256

Gnomad4 EAS exome AF: 0.0146

Gnomad4 SAS exome AF: 0.0911

Gnomad4 FIN exome AF: 0.00547

Gnomad4 NFE exome AF: 0.0271

Gnomad4 OTH exome AF: 0.0418

GnomAD4 genome AF: 0.0598 AC: 9110 AN: 152302 Hom.: 452 Cov.: 33 AF XY: 0.0594 AC XY: 4423 AN XY: 74476

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0453

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.0993

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0280

Gnomad4 OTH AF: 0.0757

Alfa AF: 0.0387 Hom.: 218

Bravo AF: 0.0636

Asia WGS AF: 0.0930 AC: 325 AN: 3478

EpiCase AF: 0.0335

EpiControl AF: 0.0341

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CCND1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	13
Dann	Benign	0.87

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: rs3862792; hg19: chr11-69462856;