NM_002293.4:c.2663T>C

Variant names:

• chr1-183125412-T-C
• rs20558
• NM_002293.4:c.2663T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002293.4(LAMC1):​c.2663T>C​(p.Leu888Pro) variant causes a missense change. The variant allele was found at a frequency of 0.566 in 1,613,112 control chromosomes in the GnomAD database, including 262,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21081 hom., cov: 31)
  • Exomes 𝑓: 0.57 (241133 hom.)
• Consequence: LAMC1 NM_002293.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.47
• Publications: 60 publications found

Genes affected

LAMC1 (HGNC:6492): (laminin subunit gamma 1) 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 1. The gamma 1 chain, formerly thought to be a beta chain, contains structural domains similar to beta chains, however, lacks the short alpha region separating domains I and II. The structural organization of this gene also suggested that it had diverged considerably from the beta chain genes. Embryos of transgenic mice in which both alleles of the gamma 1 chain gene were inactivated by homologous recombination, lacked basement membranes, indicating that laminin, gamma 1 chain is necessary for laminin heterotrimer assembly. It has been inferred by analogy with the strikingly similar 3' UTR sequence in mouse laminin gamma 1 cDNA, that multiple polyadenylation sites are utilized in human to generate the 2 different sized mRNAs (5.5 and 7.5 kb) seen on Northern analysis. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.3155422E-6).
• BP6: Variant 1-183125412-T-C is Benign according to our data. Variant chr1-183125412-T-C is described in ClinVar as Benign. ClinVar VariationId is 1290680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002293.4. 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
	LAMC1	NM_002293.4	MANE Select	c.2663T>C	p.Leu888Pro	missense	Exon 15 of 28	NP_002284.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC1	ENST00000258341.5	TSL:1 MANE Select	c.2663T>C	p.Leu888Pro	missense	Exon 15 of 28	ENSP00000258341.3	P11047
	LAMC1	ENST00000920737.1		c.2663T>C	p.Leu888Pro	missense	Exon 15 of 29	ENSP00000590796.1
	LAMC1	ENST00000920738.1		c.2654T>C	p.Leu885Pro	missense	Exon 15 of 28	ENSP00000590797.1

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78610 AN: 151888 Hom.: 21028 Cov.: 31

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.541

GnomAD2 exomes AF: 0.580 AC: 145889 AN: 251378 AF XY: 0.583

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.680

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.621

Gnomad FIN exome AF: 0.596

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.571 AC: 834916 AN: 1461106 Hom.: 241133 Cov.: 42 AF XY: 0.574 AC XY: 417360 AN XY: 726894

African (AFR) AF: 0.362 AC: 12104 AN: 33460

American (AMR) AF: 0.676 AC: 30212 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 12881 AN: 26130

East Asian (EAS) AF: 0.617 AC: 24502 AN: 39688

South Asian (SAS) AF: 0.653 AC: 56304 AN: 86242

European-Finnish (FIN) AF: 0.593 AC: 31657 AN: 53414

Middle Eastern (MID) AF: 0.541 AC: 3115 AN: 5762

European-Non Finnish (NFE) AF: 0.567 AC: 629695 AN: 1111332

Other (OTH) AF: 0.571 AC: 34446 AN: 60374

GnomAD4 genome AF: 0.518 AC: 78714 AN: 152006 Hom.: 21081 Cov.: 31 AF XY: 0.524 AC XY: 38954 AN XY: 74312

African (AFR) AF: 0.374 AC: 15499 AN: 41466

American (AMR) AF: 0.619 AC: 9447 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1728 AN: 3466

East Asian (EAS) AF: 0.610 AC: 3146 AN: 5158

South Asian (SAS) AF: 0.650 AC: 3134 AN: 4818

European-Finnish (FIN) AF: 0.603 AC: 6366 AN: 10558

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37575 AN: 67956

Other (OTH) AF: 0.547 AC: 1153 AN: 2106

Alfa AF: 0.544 Hom.: 75171

Bravo AF: 0.511

TwinsUK AF: 0.569 AC: 2111

ALSPAC AF: 0.566 AC: 2183

ESP6500AA AF: 0.374 AC: 1650

ESP6500EA AF: 0.570 AC: 4898

ExAC AF: 0.572 AC: 69468

Asia WGS AF: 0.643 AC: 2236 AN: 3478

EpiCase AF: 0.564

EpiControl AF: 0.560

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.059	T
MetaRNN	Benign	0.0000053	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.8	N
PhyloP100		4.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	5.2	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.072
MPC		0.14
ClinPred		0.0073	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.51
Mutation Taster		=97/3	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: rs20558; hg19: chr1-183094547; COSMIC: COSV51137754; COSMIC: COSV51137754;