rs3862792

Variant names:

• chr11-69648088-C-T
• rs3862792
• NM_053056.3:c.669C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_053056.3(CCND1):​c.669C>T​(p.Phe223Phe) 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:3
• Conservation: PhyloP100: 1.69
• Publications: 27 publications found

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]

CCND1 Gene-Disease associations (from GenCC):

• von Hippel-Lindau disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CCND1	NM_053056.3	c.669C>T	p.Phe223Phe	synonymous_variant	Exon 4 of 5	ENST00000227507.3	NP_444284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCND1	ENST00000227507.3	c.669C>T	p.Phe223Phe	synonymous_variant	Exon 4 of 5	1	NM_053056.3	ENSP00000227507.2
CCND1	ENST00000542367.1	n.132C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
CCND1	ENST00000545484.1	n.375C>T		non_coding_transcript_exon_variant	Exon 2 of 2	5
CCND1	ENST00000536559.1	c.*89C>T		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000438482.1

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

GnomAD2 exomes AF: 0.0393 AC: 9888 AN: 251296 AF XY: 0.0408

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 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

African (AFR) AF: 0.139 AC: 4665 AN: 33474

American (AMR) AF: 0.0258 AC: 1155 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 670 AN: 26134

East Asian (EAS) AF: 0.0146 AC: 579 AN: 39700

South Asian (SAS) AF: 0.0911 AC: 7857 AN: 86254

European-Finnish (FIN) AF: 0.00547 AC: 291 AN: 53184

Middle Eastern (MID) AF: 0.0753 AC: 434 AN: 5766

European-Non Finnish (NFE) AF: 0.0271 AC: 30178 AN: 1111968

Other (OTH) AF: 0.0418 AC: 2523 AN: 60388

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

African (AFR) AF: 0.136 AC: 5639 AN: 41536

American (AMR) AF: 0.0453 AC: 693 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3470

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5182

South Asian (SAS) AF: 0.0993 AC: 479 AN: 4824

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10626

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0280 AC: 1904 AN: 68036

Other (OTH) AF: 0.0757 AC: 160 AN: 2114

Alfa AF: 0.0414 Hom.: 323

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

CCND1-related disorder Benign:1

Jan 20, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3862792; hg19: chr11-69462856;