6-45328766-C-G

Variant names:

• chr6-45328766-C-G
• rs768149057
• NM_001024630.4:c.40C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001024630.4(RUNX2):​c.40C>G​(p.Gln14Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Q14K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38

Genes affected

RUNX2 (HGNC:10472): (RUNX family transcription factor 2) This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Two regions of potential trinucleotide repeat expansions are present in the N-terminal region of the encoded protein, and these and other mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. [provided by RefSeq, Jul 2016]

SUPT3H (HGNC:11466): (SPT3 homolog, SAGA and STAGA complex component) Enables transcription coactivator activity. Involved in histone H3 acetylation and histone deubiquitination. Located in nucleoplasm. Part of SAGA complex and transcription factor TFTC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.40C>G	p.Gln14Glu	missense_variant	Exon 2 of 9	ENST00000647337.2	NP_001019801.3
SUPT3H	NM_003599.4	c.101+36435G>C		intron_variant	Intron 2 of 10	ENST00000371459.6	NP_003590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.40C>G	p.Gln14Glu	missense_variant	Exon 2 of 9		NM_001024630.4	ENSP00000495497.1
SUPT3H	ENST00000371459.6	c.101+36435G>C		intron_variant	Intron 2 of 10	1	NM_003599.4	ENSP00000360514.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	.;T;T;T;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;.;.;D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	0.69	N;N;N;N;N;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.41	.;N;.;N;N;.
REVEL	Uncertain	0.60
Sift	Benign	0.067	.;T;.;T;T;.
Sift4G	Benign	0.37	T;T;.;T;T;T
Polyphen		0.86	.;P;P;P;.;.
Vest4		0.71
MVP		0.91
MPC		1.2
ClinPred		0.74	D
GERP RS		5.6
Varity_R		0.16
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs768149057; hg19: chr6-45296503;