6-45432657-A-G

Variant names:

• chr6-45432657-A-G
• rs2819855
• NM_001024630.4:c.580+638A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001024630.4(RUNX2):​c.580+638A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 151,906 control chromosomes in the GnomAD database, including 26,377 homozygotes. 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: 𝑓 0.59 (26377 hom., cov: 31)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 3 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.580+638A>G		intron_variant	Intron 4 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.538+638A>G		intron_variant	Intron 2 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.580+638A>G		intron_variant	Intron 4 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.538+638A>G		intron_variant	Intron 2 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.580+638A>G		intron_variant	Intron 4 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89251 AN: 151786 Hom.: 26358 Cov.: 31

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.628

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.598

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.588 AC: 89320 AN: 151906 Hom.: 26377 Cov.: 31 AF XY: 0.589 AC XY: 43699 AN XY: 74230

African (AFR) AF: 0.654 AC: 27091 AN: 41438

American (AMR) AF: 0.521 AC: 7955 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2023 AN: 3468

East Asian (EAS) AF: 0.573 AC: 2964 AN: 5172

South Asian (SAS) AF: 0.632 AC: 3044 AN: 4816

European-Finnish (FIN) AF: 0.581 AC: 6120 AN: 10534

Middle Eastern (MID) AF: 0.617 AC: 179 AN: 290

European-Non Finnish (NFE) AF: 0.561 AC: 38071 AN: 67912

Other (OTH) AF: 0.600 AC: 1262 AN: 2102

Alfa AF: 0.585 Hom.: 6568

Bravo AF: 0.584

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.3
DANN	Benign	0.77
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2819855; hg19: chr6-45400394;