rs2677104

Variant names:

• chr6-45428136-C-T
• rs2677104
• NM_001024630.4:c.424-3727C>T

Variant summary

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

The NM_001024630.4(RUNX2):​c.424-3727C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.829 in 152,146 control chromosomes in the GnomAD database, including 52,451 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 0.83 (52451 hom., cov: 33)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• Publications: 5 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=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.424-3727C>T		intron_variant	Intron 3 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.382-3727C>T		intron_variant	Intron 1 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.424-3727C>T		intron_variant	Intron 3 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.382-3727C>T		intron_variant	Intron 1 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.424-3727C>T		intron_variant	Intron 3 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.829 AC: 126027 AN: 152028 Hom.: 52398 Cov.: 33

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.933

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.812

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

GnomAD4 genome AF: 0.829 AC: 126137 AN: 152146 Hom.: 52451 Cov.: 33 AF XY: 0.831 AC XY: 61827 AN XY: 74378

African (AFR) AF: 0.801 AC: 33256 AN: 41506

American (AMR) AF: 0.751 AC: 11473 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2672 AN: 3472

East Asian (EAS) AF: 0.748 AC: 3872 AN: 5174

South Asian (SAS) AF: 0.933 AC: 4510 AN: 4834

European-Finnish (FIN) AF: 0.917 AC: 9721 AN: 10598

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 57951 AN: 67970

Other (OTH) AF: 0.814 AC: 1720 AN: 2114

Alfa AF: 0.834 Hom.: 11004

Bravo AF: 0.809

Asia WGS AF: 0.833 AC: 2888 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	7.5
DANN	Benign	0.53
PhyloP100		2.2
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: rs2677104; hg19: chr6-45395873;