rs2276092

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_015295.3(SMCHD1):c.2122G>A(p.Val708Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,602,340 control chromosomes in the GnomAD database, including 398,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38247 hom., cov: 30)

Exomes 𝑓: 0.70 ( 360236 hom. )

Consequence

SMCHD1
NM_015295.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.306

Variant links:

Genes affected

SMCHD1 (HGNC:29090): (structural maintenance of chromosomes flexible hinge domain containing 1) This gene encodes a protein which contains a hinge region domain found in members of the SMC (structural maintenance of chromosomes) protein family. [provided by RefSeq, Dec 2011]

SMCHD1 links:

ENSG00000266049 (HGNC:):

ENSG00000266049 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the SMCHD1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 3.6318 (above the threshold of 3.09). Trascript score misZ: 3.965 (above the threshold of 3.09). GenCC associations: The gene is linked to facioscapulohumeral muscular dystrophy, arhinia, choanal atresia, and microphthalmia, hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=7.739487E-7).

BP6

Variant 18-2707621-G-A is Benign according to our data. Variant chr18-2707621-G-A is described in ClinVar as [Benign]. Clinvar id is 260637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2707621-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3 link	c.2122G>A	p.Val708Ile	missense_variant	Exon 16 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11 link	c.2122G>A	p.Val708Ile	missense_variant	Exon 16 of 48	5	NM_015295.3	ENSP00000326603.7		A6NHR9-1

Frequencies

GnomAD3 genomes

AF:

0.708

AC:

107502

AN:

151768

Hom.:

38212

Cov.:

show subpopulations

Gnomad AFR

AF:

0.727

Gnomad AMI

AF:

0.802

Gnomad AMR

AF:

0.773

Gnomad ASJ

AF:

0.668

Gnomad EAS

AF:

0.612

Gnomad SAS

AF:

0.629

Gnomad FIN

AF:

0.629

Gnomad MID

AF:

0.737

Gnomad NFE

AF:

0.708

Gnomad OTH

AF:

0.712

GnomAD3 exomes

AF:

0.696

AC:

170285

AN:

244662

Hom.:

59770

AF XY:

0.689

AC XY:

91433

AN XY:

132610

show subpopulations

Gnomad AFR exome

AF:

0.722

Gnomad AMR exome

AF:

0.796

Gnomad ASJ exome

AF:

0.664

Gnomad EAS exome

AF:

0.609

Gnomad SAS exome

AF:

0.636

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.705

Gnomad OTH exome

AF:

0.712

GnomAD4 exome

AF:

0.703

AC:

1019762

AN:

1450454

Hom.:

360236

Cov.:

AF XY:

0.699

AC XY:

504671

AN XY:

721716

show subpopulations

Gnomad4 AFR exome

AF:

0.724

Gnomad4 AMR exome

AF:

0.790

Gnomad4 ASJ exome

AF:

0.656

Gnomad4 EAS exome

AF:

0.579

Gnomad4 SAS exome

AF:

0.637

Gnomad4 FIN exome

AF:

0.648

Gnomad4 NFE exome

AF:

0.712

Gnomad4 OTH exome

AF:

0.707

GnomAD4 genome

AF:

0.708

AC:

107592

AN:

151886

Hom.:

38247

Cov.:

AF XY:

0.706

AC XY:

52374

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.727

Gnomad4 AMR

AF:

0.773

Gnomad4 ASJ

AF:

0.668

Gnomad4 EAS

AF:

0.612

Gnomad4 SAS

AF:

0.628

Gnomad4 FIN

AF:

0.629

Gnomad4 NFE

AF:

0.708

Gnomad4 OTH

AF:

0.713

Alfa

AF:

0.707

Hom.:

93918

Bravo

AF:

0.722

TwinsUK

AF:

0.729

AC:

2703

ALSPAC

AF:

0.709

AC:

2734

ESP6500AA

AF:

0.730

AC:

2659

ESP6500EA

AF:

0.703

AC:

5737

ExAC

AF:

0.694

AC:

83803

Asia WGS

AF:

0.654

AC:

2275

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Mar 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Facioscapulohumeral muscular dystrophy 2

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhinia with choanal atresia and microphthalmia syndrome

Benign:1

Jul 15, 2021

Genome-Nilou Lab

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

0.059

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.7

DANN

Benign

0.82

DEOGEN2

Benign

0.080

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.21

MetaRNN

Benign

7.7e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.36

REVEL

Benign

0.038

Sift

Benign

0.49

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.020

MPC

0.53

ClinPred

0.00017

GERP RS

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.18

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over