11-69648142-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_053056.3(CCND1):c.723G>A(p.Pro241=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.444 in 1,613,168 control chromosomes in the GnomAD database, including 162,210 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12635 hom., cov: 33)
  • Exomes 𝑓: 0.45 (149575 hom.)
• Consequence: CCND1 NM_053056.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.4188
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:3
• Conservation: PhyloP100: 5.13

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 11-69648142-G-A is Benign according to our data. Variant chr11-69648142-G-A is described in ClinVar as [Benign]. Clinvar id is 13755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-69648142-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCND1	NM_053056.3	c.723G>A	p.Pro241=	splice_region_variant, synonymous_variant	4/5	ENST00000227507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCND1	ENST00000227507.3	c.723G>A	p.Pro241=	splice_region_variant, synonymous_variant	4/5	1	NM_053056.3	P1
CCND1	ENST00000542367.1	n.186G>A		splice_region_variant, non_coding_transcript_exon_variant	1/2	1
CCND1	ENST00000536559.1	c.*143G>A		3_prime_UTR_variant	2/2	3
CCND1	ENST00000545484.1	n.429G>A		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59681 AN: 152010 Hom.: 12647 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.429

GnomAD3 exomes AF: 0.453 AC: 113515 AN: 250702 Hom.: 26634 AF XY: 0.464 AC XY: 62937 AN XY: 135576

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.448

Gnomad EAS exome AF: 0.569

Gnomad SAS exome AF: 0.522

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.462

GnomAD4 exome AF: 0.449 AC: 656603 AN: 1461040 Hom.: 149575 Cov.: 43 AF XY: 0.454 AC XY: 329998 AN XY: 726820

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.379

Gnomad4 ASJ exome AF: 0.444

Gnomad4 EAS exome AF: 0.523

Gnomad4 SAS exome AF: 0.523

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.449

Gnomad4 OTH exome AF: 0.455

GnomAD4 genome AF: 0.392 AC: 59681 AN: 152128 Hom.: 12635 Cov.: 33 AF XY: 0.396 AC XY: 29472 AN XY: 74368

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.446

Gnomad4 EAS AF: 0.547

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.429

Alfa AF: 0.449 Hom.: 21060

Bravo AF: 0.380

Asia WGS AF: 0.508 AC: 1766 AN: 3478

EpiCase AF: 0.470

EpiControl AF: 0.469

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:3

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

Oct 17, 2019

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

Apr 16, 2020

This variant is associated with the following publications: (PMID: 26617896, 25997217, 16783567, 21268129, 11896626, 7675441, 10667569, 20680537, 22606291, 23502783, 21594903, 21161398, 24270739, 21107342, 17308274, 17960397, 11418364, 22304571, 20380574, 18843022, 22901215, 21273603) -

MULTIPLE MYELOMA, t(11;14) TYPE, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

Colorectal cancer, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

VON HIPPEL-LINDAU SYNDROME, MODIFIER OF Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	18
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.42
dbscSNV1_RF	Benign	0.39
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: rs9344; hg19: chr11-69462910; COSMIC: COSV57118864; COSMIC: COSV57118864;