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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291815.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMCN2	NM_001291815.2	MANE Select	c.14940C>T	p.Pro4980Pro	synonymous	Exon 98 of 98	NP_001278744.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HMCN2	ENST00000683500.2	MANE Select	c.14940C>T	p.Pro4980Pro	synonymous	Exon 98 of 98	ENSP00000508292.2
HMCN2	ENST00000624552.4	TSL:5	c.14883C>T	p.Pro4961Pro	synonymous	Exon 98 of 98	ENSP00000485357.2
HMCN2	ENST00000623487.1	TSL:2	n.3286C>T		non_coding_transcript_exon	Exon 2 of 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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over