NM_002293.4:c.2663T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.47

Publications

60 publications found

Variant links:

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]

LAMC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMC1	NM_002293.4 link	c.2663T>C	p.Leu888Pro	missense_variant	Exon 15 of 28	ENST00000258341.5	NP_002284.3	P11047Q6NVY8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMC1	ENST00000258341.5 link	c.2663T>C	p.Leu888Pro	missense_variant	Exon 15 of 28	1	NM_002293.4	ENSP00000258341.3		P11047
LAMC1	ENST00000466964.1 link	n.225T>C		non_coding_transcript_exon_variant	Exon 1 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.518

AC:

78610

AN:

151888

Hom.:

21028

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.574

AC XY:

417360

AN XY:

726894

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

17159

34318

51476

68635

85794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17614

35228

52842

70456

88070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.518

AC:

78714

AN:

152006

Hom.:

21081

Cov.:

AF XY:

0.524

AC XY:

38954

AN XY:

74312

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1891

3781

5672

7562

9453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 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

AlphaMissense

Benign

0.034

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.038

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.059

MetaRNN

Benign

0.0000053

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.8

PhyloP100

4.5

PrimateAI

Benign

0.46

PROVEAN

Benign

5.2

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.072

MPC

0.14

ClinPred

0.0073

GERP RS

5.6

Varity_R

0.11

gMVP

0.51

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over