rs190642427

Variant names:

• chr6-45328661-T-C
• rs190642427
• NM_001024630.4:c.-66T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001024630.4(RUNX2):​c.-66T>C variant causes a splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,611,312 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RUNX2 NM_001024630.4 splice_region
• Scores: Splicing: ADA: 0.1582
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.48
• Publications: 1 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]

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 6-45328661-T-C is Benign according to our data. Variant chr6-45328661-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1207597.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00149 (227/152108) while in subpopulation AFR AF = 0.00522 (217/41544). AF 95% confidence interval is 0.00465. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 227 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.-66T>C		splice_region	Exon 2 of 9	NP_001019801.3	Q13950-1
	RUNX2	NM_001024630.4	MANE Select	c.-66T>C		5_prime_UTR	Exon 2 of 9	NP_001019801.3	Q13950-1
	SUPT3H	NM_003599.4	MANE Select	c.101+36540A>G		intron	N/A	NP_003590.1	O75486-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.-66T>C		splice_region	Exon 2 of 9	ENSP00000495497.1	Q13950-1
	RUNX2	ENST00000647337.2	MANE Select	c.-66T>C		5_prime_UTR	Exon 2 of 9	ENSP00000495497.1	Q13950-1
	SUPT3H	ENST00000371459.6	TSL:1 MANE Select	c.101+36540A>G		intron	N/A	ENSP00000360514.1	O75486-1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000386 AC: 96 AN: 248712 AF XY: 0.000311

Gnomad AFR exome AF: 0.00543

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000144 AC: 210 AN: 1459204 Hom.: 0 Cov.: 31 AF XY: 0.000128 AC XY: 93 AN XY: 725966

African (AFR) AF: 0.00519 AC: 173 AN: 33342

American (AMR) AF: 0.000292 AC: 13 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110148

Other (OTH) AF: 0.000266 AC: 16 AN: 60208

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.00134 AC XY: 100 AN XY: 74354

African (AFR) AF: 0.00522 AC: 217 AN: 41544

American (AMR) AF: 0.000394 AC: 6 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67946

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000652 Hom.: 0

Bravo AF: 0.00170

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	0.99
PhyloP100		7.5
PromoterAI		0.0044	Neutral
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.38
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: rs190642427; hg19: chr6-45296398;