Genetic Variant COL21A1:p.Ser750Pro (chr6-56060995-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_030820.4(COL21A1):c.2248T>C(p.Ser750Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,610,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

COL21A1
NM_030820.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.53

Variant links:

Genes affected

COL21A1 (HGNC:17025): (collagen type XXI alpha 1 chain) This gene encodes the alpha chain of type XXI collagen, a member of the FACIT (fibril-associated collagens with interrupted helices) collagen family. Type XXI collagen is localized to tissues containing type I collagen and maintains the integrity of the extracellular matrix. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

COL21A1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055550456).

BP6

Variant 6-56060995-A-G is Benign according to our data. Variant chr6-56060995-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2609521.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL21A1	NM_030820.4 link	c.2248T>C	p.Ser750Pro	missense_variant	Exon 26 of 30	ENST00000244728.10	NP_110447.2	Q96P44-1A0A158RFW1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL21A1	ENST00000244728.10 link	c.2248T>C	p.Ser750Pro	missense_variant	Exon 26 of 30	1	NM_030820.4	ENSP00000244728.5	Q96P44-1
COL21A1	ENST00000370819.5 link	c.2239T>C	p.Ser747Pro	missense_variant	Exon 25 of 29	1		ENSP00000359855.1	Q96P44-3
COL21A1	ENST00000488912.5 link	n.*496T>C		non_coding_transcript_exon_variant	Exon 14 of 18	1		ENSP00000433624.1	H0YDH6
COL21A1	ENST00000488912.5 link	n.*496T>C		3_prime_UTR_variant	Exon 14 of 18	1		ENSP00000433624.1	H0YDH6

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000473

AC:

AN:

1457896

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

725306

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 05, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.086

T;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.043

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

-0.94

N;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

0.91

N;N;.

REVEL

Benign

0.17

Sift

Benign

0.82

T;T;.

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.046

MVP

0.32

MPC

0.021

ClinPred

0.52

GERP RS

1.7

Varity_R

0.11

gMVP

0.17

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over