NM_005190.4:c.226T>G

Variant names:

• chr6-99561435-A-C
• NM_005190.4:c.226T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005190.4(CCNC):​c.226T>G​(p.Tyr76Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCNC NM_005190.4 missense, splice_region
• Scores: Splicing: ADA: 0.008616
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13
• Publications: 0 publications found

Genes affected

CCNC (HGNC:1581): (cyclin C) The protein encoded by this gene is a member of the cyclin family of proteins. The encoded protein interacts with cyclin-dependent kinase 8 and induces the phophorylation of the carboxy-terminal domain of the large subunit of RNA polymerase II. The level of mRNAs for this gene peaks in the G1 phase of the cell cycle. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TSTD3 (HGNC:40910): (thiosulfate sulfurtransferase like domain containing 3)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005190.4. 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
	CCNC	NM_005190.4	MANE Select	c.226T>G	p.Tyr76Asp	missense splice_region	Exon 4 of 12	NP_005181.2	P24863-1
	CCNC	NM_001363537.2		c.226T>G	p.Tyr76Asp	missense splice_region	Exon 4 of 13	NP_001350466.1	E5RFK5
	CCNC	NM_001013399.2		c.-30T>G		splice_region	Exon 4 of 12	NP_001013417.1	P24863-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCNC	ENST00000520429.6	TSL:1 MANE Select	c.226T>G	p.Tyr76Asp	missense splice_region	Exon 4 of 12	ENSP00000428982.1	P24863-1
	CCNC	ENST00000369220.8	TSL:1	c.226T>G	p.Tyr76Asp	missense splice_region	Exon 4 of 12	ENSP00000358222.4	J3KP90
	CCNC	ENST00000482541.2	TSL:1	c.226T>G	p.Tyr76Asp	missense splice_region	Exon 4 of 5	ENSP00000417072.2	Q5JV82

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.040	N
REVEL	Uncertain	0.36
Sift	Benign	0.092	T
Sift4G	Benign	0.13	T
Polyphen		0.16	B
Vest4		0.80
MutPred		0.67		Loss of MoRF binding (P = 0.05)
MVP		0.87
MPC		1.7
ClinPred		0.92	D
GERP RS		3.9
PromoterAI		0.0071	Neutral
Varity_R		0.41
gMVP		0.73
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0086
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.12		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

hg19: chr6-100009311;