chr1-186182258-A-G

Variant names:

• chr1-186182258-A-G
• rs35856562
• NM_031935.3:c.16385A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_031935.3(HMCN1):​c.16385A>G​(p.Gln5462Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,613,514 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (11 hom.)
• Consequence: HMCN1 NM_031935.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.00
• Publications: 9 publications found

Genes affected

HMCN1 (HGNC:19194): (hemicentin 1) This gene encodes a large extracellular member of the immunoglobulin superfamily. A similar protein in C. elegans forms long, fine tracks at specific extracellular sites that are involved in many processes such as stabilization of the germline syncytium, anchorage of mechanosensory neurons to the epidermis, and organization of hemidesmosomes in the epidermis. Mutations in this gene may be associated with age-related macular degeneration. [provided by RefSeq, Jul 2008]

HMCN1 Gene-Disease associations (from GenCC):

• age related macular degeneration 1

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ENSG00000294274 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011597693).
• BP6: Variant 1-186182258-A-G is Benign according to our data. Variant chr1-186182258-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 781796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 286 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031935.3. 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
	HMCN1	NM_031935.3	MANE Select	c.16385A>G	p.Gln5462Arg	missense	Exon 105 of 107	NP_114141.2	Q96RW7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMCN1	ENST00000271588.9	TSL:1 MANE Select	c.16385A>G	p.Gln5462Arg	missense	Exon 105 of 107	ENSP00000271588.4	Q96RW7-1
	HMCN1	ENST00000414277.1	TSL:3	c.410A>G	p.Gln137Arg	missense	Exon 4 of 6	ENSP00000406205.1	Q5TCP6
	ENSG00000294274	ENST00000722342.1		n.238+39498T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00225 AC: 564 AN: 250760 AF XY: 0.00212

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00312

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00308 AC: 4496 AN: 1461192 Hom.: 11 Cov.: 32 AF XY: 0.00306 AC XY: 2226 AN XY: 726910

African (AFR) AF: 0.000778 AC: 26 AN: 33432

American (AMR) AF: 0.00309 AC: 138 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00636 AC: 166 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86254

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53410

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5762

European-Non Finnish (NFE) AF: 0.00352 AC: 3910 AN: 1111492

Other (OTH) AF: 0.00330 AC: 199 AN: 60356

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74488

African (AFR) AF: 0.000697 AC: 29 AN: 41580

American (AMR) AF: 0.00170 AC: 26 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00301 AC: 205 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00318 Hom.: 0

Bravo AF: 0.00215

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00217 AC: 264

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00385

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Age related macular degeneration 1 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.23	N
PhyloP100		2.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.17
Sift	Benign	0.95	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.20
MVP		0.77
MPC		0.28
ClinPred		0.012	T
GERP RS		3.1
Varity_R		0.037
gMVP		0.39
Mutation Taster		=98/2	polymorphism

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: rs35856562; hg19: chr1-186151390; COSMIC: COSV99055270; COSMIC: COSV99055270;