rs2276092

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 15/21 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

Publications

40 publications found

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 Gene-Disease associations (from GenCC):

arhinia, choanal atresia, and microphthalmia
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia, G2P
facioscapulohumeral muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SMCHD1 links:

ENSG00000266049 (HGNC:):

ENSG00000266049 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=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 VariationId is 260637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015295.3. 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
	SMCHD1	NM_015295.3	MANE Select	c.2122G>A	p.Val708Ile	missense	Exon 16 of 48	NP_056110.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.2122G>A	p.Val708Ile	missense	Exon 16 of 48	ENSP00000326603.7	A6NHR9-1
SMCHD1	ENST00000939310.1		c.2035G>A	p.Val679Ile	missense	Exon 16 of 48	ENSP00000609369.1
SMCHD1	ENST00000688342.1		c.2122G>A	p.Val708Ile	missense	Exon 16 of 47	ENSP00000508422.1	A0A8I5KRS9

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

GnomAD2 exomes

AF:

0.696

AC:

170285

AN:

244662

AF XY:

0.689

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 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

African (AFR)

AF:

0.724

AC:

23927

AN:

33030

American (AMR)

AF:

0.790

AC:

34350

AN:

43476

Ashkenazi Jewish (ASJ)

AF:

0.656

AC:

16986

AN:

25900

East Asian (EAS)

AF:

0.579

AC:

22920

AN:

39556

South Asian (SAS)

AF:

0.637

AC:

53889

AN:

84664

European-Finnish (FIN)

AF:

0.648

AC:

34482

AN:

53248

Middle Eastern (MID)

AF:

0.675

AC:

3864

AN:

5728

European-Non Finnish (NFE)

AF:

0.712

AC:

786977

AN:

1104910

Other (OTH)

AF:

0.707

AC:

42367

AN:

59942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

13427

26854

40281

53708

67135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19698

39396

59094

78792

98490

<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:

0.708

AC:

107592

AN:

151886

Hom.:

38247

Cov.:

AF XY:

0.706

AC XY:

52374

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.727

AC:

30103

AN:

41388

American (AMR)

AF:

0.773

AC:

11803

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.668

AC:

2319

AN:

3470

East Asian (EAS)

AF:

0.612

AC:

3168

AN:

5174

South Asian (SAS)

AF:

0.628

AC:

3028

AN:

4820

European-Finnish (FIN)

AF:

0.629

AC:

6621

AN:

10518

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.708

AC:

48109

AN:

67946

Other (OTH)

AF:

0.713

AC:

1498

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1547

3094

4641

6188

7735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

826

1652

2478

3304

4130

<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:

0.707

Hom.:

171752

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Arrhinia with choanal atresia and microphthalmia syndrome (1)

Facioscapulohumeral muscular dystrophy 2 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.7

(source)

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

PhyloP100

0.31

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

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over