NM_053056.3:c.724-26A>G

Variant names:

• chr11-69651092-A-G
• rs3212892
• NM_053056.3:c.724-26A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053056.3(CCND1):​c.724-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,599,804 control chromosomes in the GnomAD database, including 7,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.13 (3533 hom., cov: 33)
  • Exomes 𝑓: 0.032 (3672 hom.)
• Consequence: CCND1 NM_053056.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.03
• Publications: 7 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-69651092-A-G is Benign according to our data. Variant chr11-69651092-A-G is described in ClinVar as Benign. ClinVar VariationId is 1283485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053056.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCND1	NM_053056.3	MANE Select	c.724-26A>G		intron	N/A	NP_444284.1	P24385

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCND1	ENST00000227507.3	TSL:1 MANE Select	c.724-26A>G		intron	N/A	ENSP00000227507.2	P24385
	CCND1	ENST00000542367.1	TSL:1	n.187-26A>G		intron	N/A
	CCND1	ENST00000913508.1		c.508-26A>G		intron	N/A	ENSP00000583567.1

Frequencies

GnomAD3 genomes AF: 0.132 AC: 19889 AN: 151244 Hom.: 3515 Cov.: 33

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.0139

Gnomad EAS AF: 0.0308

Gnomad SAS AF: 0.0958

Gnomad FIN AF: 0.00333

Gnomad MID AF: 0.0641

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.0530 AC: 12108 AN: 228418 AF XY: 0.0492

Gnomad AFR exome AF: 0.397

Gnomad AMR exome AF: 0.0298

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.0280

Gnomad FIN exome AF: 0.00424

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0435

GnomAD4 exome AF: 0.0324 AC: 46918 AN: 1448446 Hom.: 3672 Cov.: 31 AF XY: 0.0329 AC XY: 23695 AN XY: 720082

African (AFR) AF: 0.414 AC: 13452 AN: 32502

American (AMR) AF: 0.0330 AC: 1431 AN: 43406

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 378 AN: 25630

East Asian (EAS) AF: 0.0257 AC: 988 AN: 38436

South Asian (SAS) AF: 0.0869 AC: 7352 AN: 84578

European-Finnish (FIN) AF: 0.00455 AC: 240 AN: 52706

Middle Eastern (MID) AF: 0.0797 AC: 457 AN: 5732

European-Non Finnish (NFE) AF: 0.0176 AC: 19511 AN: 1105712

Other (OTH) AF: 0.0520 AC: 3109 AN: 59744

GnomAD4 genome AF: 0.132 AC: 19968 AN: 151358 Hom.: 3533 Cov.: 33 AF XY: 0.129 AC XY: 9549 AN XY: 73922

African (AFR) AF: 0.405 AC: 16747 AN: 41300

American (AMR) AF: 0.0577 AC: 879 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 48 AN: 3458

East Asian (EAS) AF: 0.0308 AC: 158 AN: 5126

South Asian (SAS) AF: 0.0953 AC: 453 AN: 4754

European-Finnish (FIN) AF: 0.00333 AC: 35 AN: 10520

Middle Eastern (MID) AF: 0.0664 AC: 19 AN: 286

European-Non Finnish (NFE) AF: 0.0203 AC: 1377 AN: 67682

Other (OTH) AF: 0.115 AC: 241 AN: 2096

Alfa AF: 0.0997 Hom.: 774

Bravo AF: 0.143

Asia WGS AF: 0.117 AC: 405 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.68
DANN	Benign	0.18
PhyloP100		-2.0
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3212892; hg19: chr11-69465860; COSMIC: COSV57119935; COSMIC: COSV57119935;