rs2228548

Variant names:

• chr6-116120307-C-G
• rs2228548
• NM_000493.4:c.1809G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000493.4(COL10A1):​c.1809G>C​(p.Val603Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,614,142 control chromosomes in the GnomAD database, including 2,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (167 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2527 hom.)
• Consequence: COL10A1 NM_000493.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.102
• Publications: 7 publications found

Genes affected

COL10A1 (HGNC:2185): (collagen type X alpha 1 chain) This gene encodes the alpha chain of type X collagen, a short chain collagen expressed by hypertrophic chondrocytes during endochondral ossification. Unlike type VIII collagen, the other short chain collagen, type X collagen is a homotrimer. Mutations in this gene are associated with Schmid type metaphyseal chondrodysplasia (SMCD) and Japanese type spondylometaphyseal dysplasia (SMD). [provided by RefSeq, Jul 2008]

NT5DC1 (HGNC:21556): (5'-nucleotidase domain containing 1) While the exact function of the protein encoded by this gene is not known, it belongs to the 5'(3')-deoxyribonucleotidase family. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 6-116120307-C-G is Benign according to our data. Variant chr6-116120307-C-G is described in ClinVar as Benign. ClinVar VariationId is 256261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.102 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0569 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000493.4. 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
	COL10A1	NM_000493.4	MANE Select	c.1809G>C	p.Val603Val	synonymous	Exon 3 of 3	NP_000484.2
	NT5DC1	NM_152729.3	MANE Select	c.529+2362C>G		intron	N/A	NP_689942.2
	COL10A1	NM_001424106.1		c.1809G>C	p.Val603Val	synonymous	Exon 3 of 3	NP_001411035.1	A0A650AXN9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL10A1	ENST00000651968.1	MANE Select	c.1809G>C	p.Val603Val	synonymous	Exon 3 of 3	ENSP00000498802.1	Q03692
	COL10A1	ENST00000243222.8	TSL:1	c.1809G>C	p.Val603Val	synonymous	Exon 3 of 3	ENSP00000243222.4	Q03692
	COL10A1	ENST00000327673.4	TSL:1	c.1809G>C	p.Val603Val	synonymous	Exon 2 of 2	ENSP00000327368.4	Q03692

Frequencies

GnomAD3 genomes AF: 0.0443 AC: 6743 AN: 152164 Hom.: 166 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.0562

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0585

Gnomad OTH AF: 0.0335

GnomAD2 exomes AF: 0.0436 AC: 10960 AN: 251476 AF XY: 0.0452

Gnomad AFR exome AF: 0.0330

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0645

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0564

Gnomad NFE exome AF: 0.0579

Gnomad OTH exome AF: 0.0438

GnomAD4 exome AF: 0.0556 AC: 81329 AN: 1461860 Hom.: 2527 Cov.: 37 AF XY: 0.0553 AC XY: 40181 AN XY: 727234

African (AFR) AF: 0.0307 AC: 1027 AN: 33480

American (AMR) AF: 0.0192 AC: 859 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0642 AC: 1678 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0365 AC: 3151 AN: 86256

European-Finnish (FIN) AF: 0.0577 AC: 3082 AN: 53420

Middle Eastern (MID) AF: 0.0669 AC: 386 AN: 5768

European-Non Finnish (NFE) AF: 0.0611 AC: 67960 AN: 1111980

Other (OTH) AF: 0.0527 AC: 3181 AN: 60396

GnomAD4 genome AF: 0.0443 AC: 6748 AN: 152282 Hom.: 167 Cov.: 32 AF XY: 0.0426 AC XY: 3172 AN XY: 74460

African (AFR) AF: 0.0322 AC: 1336 AN: 41550

American (AMR) AF: 0.0225 AC: 345 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0364 AC: 176 AN: 4832

European-Finnish (FIN) AF: 0.0562 AC: 596 AN: 10600

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0585 AC: 3977 AN: 68022

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.0558 Hom.: 207

Bravo AF: 0.0416

Asia WGS AF: 0.0160 AC: 56 AN: 3478

EpiCase AF: 0.0551

EpiControl AF: 0.0573

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Metaphyseal chondrodysplasia, Schmid type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.6
DANN	Benign	0.79
PhyloP100		0.10
Mutation Taster		=98/2	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: rs2228548; hg19: chr6-116441470; COSMIC: COSV54574975; COSMIC: COSV54574975;