chr18-2656249-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015295.3(SMCHD1):c.174G>C(p.Ala58Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,489,176 control chromosomes in the GnomAD database, including 241,052 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A58A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.63 ( 32063 hom., cov: 33)

Exomes 𝑓: 0.55 ( 208989 hom. )

Consequence

SMCHD1
NM_015295.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.813

Publications

17 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, ClinGen, Illumina
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 18-2656249-G-C is Benign according to our data. Variant chr18-2656249-G-C is described in ClinVar as Benign. ClinVar VariationId is 260632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.813 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.842 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	NM_015295.3	MANE Select	c.174G>C	p.Ala58Ala	synonymous	Exon 1 of 48	NP_056110.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.174G>C	p.Ala58Ala	synonymous	Exon 1 of 48	ENSP00000326603.7
SMCHD1	ENST00000688342.1		c.174G>C	p.Ala58Ala	synonymous	Exon 1 of 47	ENSP00000508422.1
SMCHD1	ENST00000684915.1		n.331G>C		non_coding_transcript_exon	Exon 1 of 14

Frequencies

GnomAD3 genomes

AF:

0.633

AC:

96332

AN:

152064

Hom.:

32011

Cov.:

show subpopulations

Gnomad AFR

AF:

0.849

Gnomad AMI

AF:

0.646

Gnomad AMR

AF:

0.575

Gnomad ASJ

AF:

0.655

Gnomad EAS

AF:

0.343

Gnomad SAS

AF:

0.639

Gnomad FIN

AF:

0.570

Gnomad MID

AF:

0.672

Gnomad NFE

AF:

0.545

Gnomad OTH

AF:

0.631

GnomAD2 exomes

AF:

0.558

AC:

82317

AN:

147528

AF XY:

0.557

show subpopulations

Gnomad AFR exome

AF:

0.851

Gnomad AMR exome

AF:

0.539

Gnomad ASJ exome

AF:

0.640

Gnomad EAS exome

AF:

0.319

Gnomad FIN exome

AF:

0.547

Gnomad NFE exome

AF:

0.533

Gnomad OTH exome

AF:

0.565

GnomAD4 exome

AF:

0.555

AC:

741595

AN:

1336994

Hom.:

208989

Cov.:

AF XY:

0.557

AC XY:

368498

AN XY:

661722

show subpopulations

African (AFR)

AF:

0.873

AC:

22825

AN:

26160

American (AMR)

AF:

0.554

AC:

11285

AN:

20366

Ashkenazi Jewish (ASJ)

AF:

0.655

AC:

14518

AN:

22162

East Asian (EAS)

AF:

0.334

AC:

10580

AN:

31658

South Asian (SAS)

AF:

0.631

AC:

43681

AN:

69266

European-Finnish (FIN)

AF:

0.554

AC:

25862

AN:

46680

Middle Eastern (MID)

AF:

0.674

AC:

3605

AN:

5348

European-Non Finnish (NFE)

AF:

0.545

AC:

577686

AN:

1060444

Other (OTH)

AF:

0.575

AC:

31553

AN:

54910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

16142

32284

48426

64568

80710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16904

33808

50712

67616

84520

<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:

0.634

AC:

96443

AN:

152182

Hom.:

32063

Cov.:

AF XY:

0.632

AC XY:

47043

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.849

AC:

35286

AN:

41540

American (AMR)

AF:

0.576

AC:

8810

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.655

AC:

2275

AN:

3472

East Asian (EAS)

AF:

0.342

AC:

1770

AN:

5172

South Asian (SAS)

AF:

0.638

AC:

3080

AN:

4828

European-Finnish (FIN)

AF:

0.570

AC:

6038

AN:

10588

Middle Eastern (MID)

AF:

0.678

AC:

198

AN:

292

European-Non Finnish (NFE)

AF:

0.545

AC:

37066

AN:

67972

Other (OTH)

AF:

0.631

AC:

1332

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1729

3458

5187

6916

8645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

762

1524

2286

3048

3810

<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:

0.448

Hom.:

1129

Bravo

AF:

0.642

Asia WGS

AF:

0.520

AC:

1810

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 18, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 29, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 23, 2016

Eurofins Ntd Llc (ga)

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.1

(source)

DANN

Benign

0.51

PhyloP100

-0.81

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over