rs11498198

Variant names:

• chr6-45547270-G-A
• rs11498198
• NM_001024630.4:c.1531G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-45547270-G-A
• chr6-45547270-G-C
• chr6-45547270-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001024630.4(RUNX2):​c.1531G>A​(p.Gly511Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,152 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (87 hom.)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.60
• Publications: 11 publications found

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]

RUNX2 Gene-Disease associations (from GenCC):

• cleidocranial dysplasia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia, Orphanet
• metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.6033 (below the threshold of 3.09). Trascript score misZ: 1.7818 (below the threshold of 3.09). GenCC associations: The gene is linked to cleidocranial dysplasia 1, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008539617).
• BP6: Variant 6-45547270-G-A is Benign according to our data. Variant chr6-45547270-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0083 (1264/152302) while in subpopulation NFE AF = 0.0114 (777/68030). AF 95% confidence interval is 0.0108. There are 8 homozygotes in GnomAd4. There are 620 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1264 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024630.4. 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
	RUNX2	NM_001024630.4	MANE Select	c.1531G>A	p.Gly511Ser	missense	Exon 9 of 9	NP_001019801.3	Q13950-1
	RUNX2	NM_001369405.1		c.1489G>A	p.Gly497Ser	missense	Exon 7 of 7	NP_001356334.1	Q13950-2
	RUNX2	NM_001015051.4		c.1465G>A	p.Gly489Ser	missense	Exon 8 of 8	NP_001015051.3	Q13950-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.1531G>A	p.Gly511Ser	missense	Exon 9 of 9	ENSP00000495497.1	Q13950-1
	RUNX2	ENST00000359524.7	TSL:1	c.1489G>A	p.Gly497Ser	missense	Exon 7 of 7	ENSP00000352514.5	Q13950-2
	RUNX2	ENST00000625924.1	TSL:1	c.1423G>A	p.Gly475Ser	missense	Exon 6 of 6	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1264 AN: 152184 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00764 AC: 1919 AN: 251052 AF XY: 0.00792

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00996

GnomAD4 exome AF: 0.0106 AC: 15454 AN: 1461850 Hom.: 87 Cov.: 31 AF XY: 0.0103 AC XY: 7514 AN XY: 727228

African (AFR) AF: 0.00373 AC: 125 AN: 33480

American (AMR) AF: 0.00463 AC: 207 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26136

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

South Asian (SAS) AF: 0.00196 AC: 169 AN: 86256

European-Finnish (FIN) AF: 0.0121 AC: 649 AN: 53420

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5766

European-Non Finnish (NFE) AF: 0.0123 AC: 13649 AN: 1111974

Other (OTH) AF: 0.00972 AC: 587 AN: 60394

GnomAD4 genome AF: 0.00830 AC: 1264 AN: 152302 Hom.: 8 Cov.: 32 AF XY: 0.00832 AC XY: 620 AN XY: 74478

African (AFR) AF: 0.00440 AC: 183 AN: 41556

American (AMR) AF: 0.00713 AC: 109 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0150 AC: 159 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 777 AN: 68030

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00936 Hom.: 22

Bravo AF: 0.00804

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.00812 AC: 986

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Cleidocranial dysostosis (2)
-	-	1	Cleidocranial dysostosis;C3549874:Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.33
Sift	Benign	0.070	T
Sift4G	Benign	0.096	T
Polyphen		1.0	D
Vest4		0.46
MVP		0.56
MPC		1.6
ClinPred		0.016	T
GERP RS		5.8
Varity_R		0.49
gMVP		0.48
Mutation Taster		=42/58	disease causing

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: rs11498198; hg19: chr6-45515007;