NM_053056.3:c.800A>G

Variant names:

• chr11-69651194-A-G
• rs377271027
• NM_053056.3:c.800A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_053056.3(CCND1):​c.800A>G​(p.Asp267Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000908 in 1,608,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: CCND1 NM_053056.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17972085).
• BS2: High AC in GnomAd4 at 8 AD gene.

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.800A>G	p.Asp267Gly	missense	Exon 5 of 5	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.800A>G	p.Asp267Gly	missense	Exon 5 of 5	ENSP00000227507.2	P24385
	CCND1	ENST00000542367.1	TSL:1	n.263A>G		non_coding_transcript_exon	Exon 2 of 2
	CCND1	ENST00000913508.1		c.584A>G	p.Asp195Gly	missense	Exon 4 of 4	ENSP00000583567.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152006 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000288 AC: 7 AN: 243242 AF XY: 0.0000302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000647

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000947 AC: 138 AN: 1456680 Hom.: 0 Cov.: 32 AF XY: 0.0000939 AC XY: 68 AN XY: 724340

African (AFR) AF: 0.00 AC: 0 AN: 33074

American (AMR) AF: 0.00 AC: 0 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39108

South Asian (SAS) AF: 0.00 AC: 0 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1109158

Other (OTH) AF: 0.000133 AC: 8 AN: 60162

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152006 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74256

African (AFR) AF: 0.0000242 AC: 1 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.022
Sift	Benign	0.35	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.70
MPC		0.98
ClinPred		0.10	T
GERP RS		3.6
Varity_R		0.32
gMVP		0.14
Mutation Taster		=81/19	polymorphism

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: rs377271027; hg19: chr11-69465962; COSMIC: COSV105846873;