chr11-69641449-A-C

Variant names:

• chr11-69641449-A-C
• rs747665638
• NM_053056.3:c.136A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_053056.3(CCND1):​c.136A>C​(p.Lys46Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K46E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCND1 NM_053056.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.39
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29870954).

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.136A>C	p.Lys46Gln	missense	Exon 1 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.136A>C	p.Lys46Gln	missense	Exon 1 of 5	ENSP00000227507.2	P24385
	CCND1	ENST00000913508.1		c.136A>C	p.Lys46Gln	missense	Exon 1 of 4	ENSP00000583567.1
	CCND1	ENST00000536559.1	TSL:3	c.136A>C	p.Lys46Gln	missense	Exon 1 of 2	ENSP00000438482.1	F5H437

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461164 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726896

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.43	N
PhyloP100		6.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.34	T
Sift4G	Benign	0.40	T
Polyphen		0.014	B
Vest4		0.35
MutPred		0.40		Loss of methylation at K46 (P = 6e-04)
MVP		0.68
MPC		1.8
ClinPred		0.83	D
GERP RS		4.1
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.34
Mutation Taster		=50/50

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: rs747665638; hg19: chr11-69456217; COSMIC: COSV108091289; COSMIC: COSV108091289;