dbSNP rs3749864: RUNX2:c.423+39G>A (chr6-45422996-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001024630.4(RUNX2):c.423+39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,116 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.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RUNX2
NM_001024630.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.45

Publications

1 publications found

Variant links:

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

RUNX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4 link	c.423+39G>A	intron_variant	Intron 3 of 8	ENST00000647337.2	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1 link	c.381+39G>A	intron_variant	Intron 1 of 6		NP_001356334.1
RUNX2	NM_001015051.4 link	c.423+39G>A	intron_variant	Intron 3 of 7		NP_001015051.3	Q13950-3
RUNX2	NM_001278478.2 link	c.381+39G>A	intron_variant	Intron 1 of 5		NP_001265407.1	Q32MY8A0A0D9SEN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2 link	c.423+39G>A		intron_variant	Intron 3 of 8		NM_001024630.4	ENSP00000495497.1		Q13950-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000952

AC:

AN:

210156

AF XY:

0.00000855

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000618

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1440116

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32986

American (AMR)

AF:

0.0000230

AC:

AN:

43532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25706

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38808

South Asian (SAS)

AF:

0.00

AC:

AN:

84992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4158

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104532

Other (OTH)

AF:

0.00

AC:

AN:

59440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.6

(source)

DANN

Uncertain

0.98

PhyloP100

-1.4

PromoterAI

-0.034

Neutral

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over