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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL10A1	NM_000493.4	c.1809G>C	p.Val603Val	synonymous_variant	Exon 3 of 3	ENST00000651968.1	NP_000484.2
NT5DC1	NM_152729.3	c.529+2362C>G		intron_variant	Intron 6 of 11	ENST00000319550.9	NP_689942.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL10A1	ENST00000651968.1	c.1809G>C	p.Val603Val	synonymous_variant	Exon 3 of 3		NM_000493.4	ENSP00000498802.1
NT5DC1	ENST00000319550.9	c.529+2362C>G		intron_variant	Intron 6 of 11	1	NM_152729.3	ENSP00000326858.3

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Metaphyseal chondrodysplasia, Schmid type Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;