chr1-186119940-G-A

Variant names:

• chr1-186119940-G-A
• rs2891230
• NM_031935.3:c.12094+58G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031935.3(HMCN1):​c.12094+58G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,613,322 control chromosomes in the GnomAD database, including 98,937 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 0.34 (9092 hom., cov: 32)
  • Exomes 𝑓: 0.34 (89845 hom.)
• Consequence: HMCN1 NM_031935.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 13 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMCN1	NM_031935.3	c.12094+58G>A		intron_variant	Intron 79 of 106	ENST00000271588.9	NP_114141.2
HMCN1	XM_011510038.4	c.12094+58G>A		intron_variant	Intron 79 of 105		XP_011508340.1
HMCN1	XM_017002437.2	c.10117+58G>A		intron_variant	Intron 68 of 95		XP_016857926.1
HMCN1	XM_047431608.1	c.7918+58G>A		intron_variant	Intron 56 of 83		XP_047287564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMCN1	ENST00000271588.9	c.12094+58G>A		intron_variant	Intron 79 of 106	1	NM_031935.3	ENSP00000271588.4

Frequencies

GnomAD3 genomes AF: 0.336 AC: 50999 AN: 151704 Hom.: 9060 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.345 AC: 504216 AN: 1461508 Hom.: 89845 Cov.: 37 AF XY: 0.346 AC XY: 251919 AN XY: 727062

African (AFR) AF: 0.260 AC: 8684 AN: 33458

American (AMR) AF: 0.557 AC: 24896 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 8695 AN: 26128

East Asian (EAS) AF: 0.521 AC: 20697 AN: 39694

South Asian (SAS) AF: 0.402 AC: 34636 AN: 86222

European-Finnish (FIN) AF: 0.378 AC: 20208 AN: 53414

Middle Eastern (MID) AF: 0.383 AC: 2206 AN: 5766

European-Non Finnish (NFE) AF: 0.327 AC: 363099 AN: 1111746

Other (OTH) AF: 0.349 AC: 21095 AN: 60384

GnomAD4 genome AF: 0.336 AC: 51060 AN: 151814 Hom.: 9092 Cov.: 32 AF XY: 0.342 AC XY: 25369 AN XY: 74166

African (AFR) AF: 0.251 AC: 10409 AN: 41392

American (AMR) AF: 0.462 AC: 7055 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1133 AN: 3468

East Asian (EAS) AF: 0.547 AC: 2822 AN: 5162

South Asian (SAS) AF: 0.415 AC: 1994 AN: 4802

European-Finnish (FIN) AF: 0.386 AC: 4038 AN: 10466

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22598 AN: 67944

Other (OTH) AF: 0.345 AC: 728 AN: 2112

Alfa AF: 0.353 Hom.: 1564

Bravo AF: 0.342

Asia WGS AF: 0.465 AC: 1616 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.4
DANN	Benign	0.62
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2891230; hg19: chr1-186089072; COSMIC: COSV54917719;