rs2296291

Variant names:

• chr1-183110374-C-T
• rs2296291
• NM_002293.4:c.855-114C>T

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.855-114C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 735,432 control chromosomes in the GnomAD database, including 116,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21031 hom., cov: 32)
  • Exomes 𝑓: 0.57 (95786 hom.)
• Consequence: LAMC1 NM_002293.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.562
• Publications: 9 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 (BayesDel_noAF=-0.97).
• BP6: Variant 1-183110374-C-T is Benign according to our data. Variant chr1-183110374-C-T is described in ClinVar as Benign. ClinVar VariationId is 1250945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMC1	NM_002293.4	c.855-114C>T		intron_variant	Intron 3 of 27	ENST00000258341.5	NP_002284.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5	c.855-114C>T		intron_variant	Intron 3 of 27	1	NM_002293.4	ENSP00000258341.3
LAMC1	ENST00000484114.2	c.-31-114C>T		intron_variant	Intron 3 of 3	3		ENSP00000473583.1
LAMC1	ENST00000479499.1	n.-207C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78531 AN: 151884 Hom.: 20978 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.541

GnomAD4 exome AF: 0.569 AC: 331706 AN: 583430 Hom.: 95786 AF XY: 0.571 AC XY: 172177 AN XY: 301598

African (AFR) AF: 0.362 AC: 5196 AN: 14338

American (AMR) AF: 0.665 AC: 14116 AN: 21226

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 6872 AN: 14176

East Asian (EAS) AF: 0.619 AC: 19691 AN: 31824

South Asian (SAS) AF: 0.646 AC: 23845 AN: 36906

European-Finnish (FIN) AF: 0.589 AC: 25143 AN: 42672

Middle Eastern (MID) AF: 0.533 AC: 1968 AN: 3694

European-Non Finnish (NFE) AF: 0.561 AC: 218365 AN: 389086

Other (OTH) AF: 0.560 AC: 16510 AN: 29508

GnomAD4 genome AF: 0.517 AC: 78634 AN: 152002 Hom.: 21031 Cov.: 32 AF XY: 0.524 AC XY: 38918 AN XY: 74290

African (AFR) AF: 0.375 AC: 15521 AN: 41444

American (AMR) AF: 0.618 AC: 9453 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1720 AN: 3472

East Asian (EAS) AF: 0.612 AC: 3165 AN: 5168

South Asian (SAS) AF: 0.649 AC: 3130 AN: 4820

European-Finnish (FIN) AF: 0.603 AC: 6358 AN: 10536

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

European-Non Finnish (NFE) AF: 0.551 AC: 37463 AN: 67962

Other (OTH) AF: 0.547 AC: 1156 AN: 2114

Alfa AF: 0.514 Hom.: 2672

Bravo AF: 0.510

Asia WGS AF: 0.642 AC: 2232 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.8
DANN	Benign	0.44
PhyloP100		0.56
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: rs2296291; hg19: chr1-183079509; COSMIC: COSV107250171; COSMIC: COSV107250171;