dbSNP rs201631086: SMCHD1:c.424+10C>T (chr18-2667041-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015295.3(SMCHD1):c.424+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,547,264 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

SMCHD1
NM_015295.3 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: -0.229

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 18-2667041-C-T is Benign according to our data. Variant chr18-2667041-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260649.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00208 (317/152234) while in subpopulation AFR AF = 0.0071 (295/41542). AF 95% confidence interval is 0.00643. There are 1 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 317 AD gene.

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.424+10C>T		intron	N/A	NP_056110.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.424+10C>T	intron	N/A	ENSP00000326603.7	A6NHR9-1
SMCHD1	ENST00000939310.1		c.424+10C>T	intron	N/A	ENSP00000609369.1
SMCHD1	ENST00000688342.1		c.424+10C>T	intron	N/A	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00715

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000499

AC:

AN:

170314

AF XY:

0.000420

show subpopulations

Gnomad AFR exome

AF:

0.00703

Gnomad AMR exome

AF:

0.000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.000855

GnomAD4 exome

AF:

0.000219

AC:

305

AN:

1395030

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

126

AN XY:

688484

show subpopulations

African (AFR)

AF:

0.00789

AC:

252

AN:

31920

American (AMR)

AF:

0.000499

AC:

AN:

36050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24942

East Asian (EAS)

AF:

0.00

AC:

AN:

37042

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49882

Middle Eastern (MID)

AF:

0.000355

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00000466

AC:

AN:

1071972

Other (OTH)

AF:

0.000449

AC:

AN:

57866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00208

AC:

317

AN:

152234

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00710

AC:

295

AN:

41542

American (AMR)

AF:

0.000981

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00202

Hom.:

Bravo

AF:

0.00236

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Facioscapulohumeral muscular dystrophy 2 (2)

not provided (1)

not specified (1)

SMCHD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.29

(source)

DANN

Benign

0.65

PhyloP100

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Computational scores

Splicing

Publications

Other links and lift over