Genetic Variant HMCN2:p.Pro4980Pro (chr9-130433393-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_001291815.2(HMCN2):c.14940C>T(p.Pro4980Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,486,742 control chromosomes in the GnomAD database, including 108,950 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 0.35 ( 9879 hom., cov: 34)

Exomes 𝑓: 0.38 ( 99071 hom. )

Consequence

HMCN2
NM_001291815.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0660

Publications

7 publications found

Variant links:

Genes affected

HMCN2 (HGNC:21293): (hemicentin 2) Predicted to enable calcium ion binding activity. Predicted to be an extracellular matrix structural constituent. Predicted to be involved in cell adhesion. Located in collagen-containing extracellular matrix. [provided by Alliance of Genome Resources, Apr 2022]

HMCN2 links:

LOC107987134 (HGNC:):

LOC107987134 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP7

Synonymous conserved (PhyloP=0.066 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMCN2	NM_001291815.2 link	c.14940C>T	p.Pro4980Pro	synonymous_variant	Exon 98 of 98	ENST00000683500.2	NP_001278744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
HMCN2	ENST00000683500.2 link	c.14940C>T	p.Pro4980Pro	synonymous_variant	Exon 98 of 98		NM_001291815.2	ENSP00000508292.2
HMCN2	ENST00000624552.4 link	c.14883C>T	p.Pro4961Pro	synonymous_variant	Exon 98 of 98	5		ENSP00000485357.2
HMCN2	ENST00000623487.1 link	n.3286C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.354

AC:

53781

AN:

152018

Hom.:

9878

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.386

Gnomad AMR

AF:

0.303

Gnomad ASJ

AF:

0.376

Gnomad EAS

AF:

0.343

Gnomad SAS

AF:

0.351

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.375

Gnomad NFE

AF:

0.394

Gnomad OTH

AF:

0.355

GnomAD2 exomes

AF:

0.341

AC:

29921

AN:

87770

AF XY:

0.349

show subpopulations

Gnomad AFR exome

AF:

0.296

Gnomad AMR exome

AF:

0.219

Gnomad ASJ exome

AF:

0.382

Gnomad EAS exome

AF:

0.332

Gnomad FIN exome

AF:

0.401

Gnomad NFE exome

AF:

0.391

Gnomad OTH exome

AF:

0.347

GnomAD4 exome

AF:

0.383

AC:

511457

AN:

1334610

Hom.:

99071

Cov.:

AF XY:

0.382

AC XY:

251148

AN XY:

657030

show subpopulations

African (AFR)

AF:

0.293

AC:

7887

AN:

26912

American (AMR)

AF:

0.233

AC:

6881

AN:

29534

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

9038

AN:

23440

East Asian (EAS)

AF:

0.357

AC:

10620

AN:

29782

South Asian (SAS)

AF:

0.345

AC:

25553

AN:

74042

European-Finnish (FIN)

AF:

0.399

AC:

13218

AN:

33134

Middle Eastern (MID)

AF:

0.422

AC:

1789

AN:

4242

European-Non Finnish (NFE)

AF:

0.393

AC:

415470

AN:

1057986

Other (OTH)

AF:

0.378

AC:

21001

AN:

55538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

18585

37171

55756

74342

92927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13186

26372

39558

52744

65930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.354

AC:

53782

AN:

152132

Hom.:

9879

Cov.:

AF XY:

0.356

AC XY:

26468

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.289

AC:

12019

AN:

41522

American (AMR)

AF:

0.303

AC:

4634

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.376

AC:

1306

AN:

3470

East Asian (EAS)

AF:

0.342

AC:

1758

AN:

5134

South Asian (SAS)

AF:

0.351

AC:

1691

AN:

4822

European-Finnish (FIN)

AF:

0.413

AC:

4383

AN:

10604

Middle Eastern (MID)

AF:

0.386

AC:

112

AN:

290

European-Non Finnish (NFE)

AF:

0.394

AC:

26783

AN:

67966

Other (OTH)

AF:

0.352

AC:

745

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1821

3643

5464

7286

9107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.372

Hom.:

1958

Bravo

AF:

0.340

Asia WGS

AF:

0.334

AC:

1161

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.4

(source)

DANN

Benign

0.96

PhyloP100

0.066

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over