rs549191

Variant names:

• chr1-183251802-A-G
• rs549191
• NM_015039.4:c.*839T>C

Variant summary

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

The NM_015039.4(NMNAT2):​c.*839T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 157,018 control chromosomes in the GnomAD database, including 7,595 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 0.28 (7577 hom., cov: 32)
  • Exomes 𝑓: 0.075 (18 hom.)
• Consequence: NMNAT2 NM_015039.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.958
• Publications: 8 publications found

Genes affected

NMNAT2 (HGNC:16789): (nicotinamide nucleotide adenylyltransferase 2) This gene product belongs to the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme family, members of which catalyze an essential step in NAD (NADP) biosynthetic pathway. Unlike the other human family member, which is localized to the nucleus, and is ubiquitously expressed; this enzyme is cytoplasmic, and is predominantly expressed in the brain. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

LAMC2 (HGNC:6493): (laminin subunit gamma 2) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), have a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the gamma chain isoform laminin, gamma 2. The gamma 2 chain, formerly thought to be a truncated version of beta chain (B2t), is highly homologous to the gamma 1 chain; however, it lacks domain VI, and domains V, IV and III are shorter. It is expressed in several fetal tissues but differently from gamma 1, and is specifically localized to epithelial cells in skin, lung and kidney. The gamma 2 chain together with alpha 3 and beta 3 chains constitute laminin 5 (earlier known as kalinin), which is an integral part of the anchoring filaments that connect epithelial cells to the underlying basement membrane. The epithelium-specific expression of the gamma 2 chain implied its role as an epithelium attachment molecule, and mutations in this gene have been associated with junctional epidermolysis bullosa, a skin disease characterized by blisters due to disruption of the epidermal-dermal junction. Two transcript variants resulting from alternative splicing of the 3' terminal exon, and encoding different isoforms of gamma 2 chain, have been described. The two variants are differentially expressed in embryonic tissues, however, the biological significance of the two forms is not known. Transcript variants utilizing alternative polyA_signal have also been noted in literature. [provided by RefSeq, Aug 2011]

LAMC2 Gene-Disease associations (from GenCC):

• junctional epidermolysis bullosa

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• junctional epidermolysis bullosa Herlitz type

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, PanelApp Australia
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, PanelApp Australia
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NMNAT2	NM_015039.4	c.*839T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000287713.7	NP_055854.1
NMNAT2	NM_170706.4	c.*839T>C		3_prime_UTR_variant	Exon 11 of 11		NP_733820.1
LAMC2	XM_047420358.1	c.3329-6307A>G		intron_variant	Intron 22 of 23		XP_047276314.1
LAMC2	XM_047420361.1	c.3329-6920A>G		intron_variant	Intron 22 of 22		XP_047276317.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NMNAT2	ENST00000287713.7	c.*839T>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_015039.4	ENSP00000287713.6
NMNAT2	ENST00000294868.8	c.*839T>C		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000294868.4

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42908 AN: 152024 Hom.: 7541 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.0753 AC: 367 AN: 4876 Hom.: 18 Cov.: 0 AF XY: 0.0786 AC XY: 220 AN XY: 2798

African (AFR) AF: 0.194 AC: 14 AN: 72

American (AMR) AF: 0.0473 AC: 7 AN: 148

Ashkenazi Jewish (ASJ) AF: 0.0405 AC: 3 AN: 74

East Asian (EAS) AF: 0.192 AC: 10 AN: 52

South Asian (SAS) AF: 0.0572 AC: 51 AN: 892

European-Finnish (FIN) AF: 0.117 AC: 70 AN: 598

Middle Eastern (MID) AF: 0.0666 AC: 39 AN: 586

European-Non Finnish (NFE) AF: 0.0642 AC: 141 AN: 2196

Other (OTH) AF: 0.124 AC: 32 AN: 258

GnomAD4 genome AF: 0.283 AC: 43007 AN: 152142 Hom.: 7577 Cov.: 32 AF XY: 0.284 AC XY: 21117 AN XY: 74384

African (AFR) AF: 0.486 AC: 20142 AN: 41478

American (AMR) AF: 0.299 AC: 4569 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 581 AN: 3470

East Asian (EAS) AF: 0.374 AC: 1928 AN: 5160

South Asian (SAS) AF: 0.313 AC: 1510 AN: 4818

European-Finnish (FIN) AF: 0.168 AC: 1780 AN: 10598

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11853 AN: 68008

Other (OTH) AF: 0.238 AC: 503 AN: 2110

Alfa AF: 0.207 Hom.: 10356

Bravo AF: 0.302

Asia WGS AF: 0.346 AC: 1202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.7
DANN	Benign	0.69
PhyloP100		0.96
Mutation Taster		=100/0	polymorphism (auto)

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: rs549191; hg19: chr1-183220937;