GeneBe

18-2667015-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_015295.3(SMCHD1):​c.408A>G​(p.Glu136Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000209 in 1,433,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SMCHD1
NM_015295.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.00

Publications

2 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.44).
BP6
Variant 18-2667015-A-G is Benign according to our data. Variant chr18-2667015-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 759255.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMCHD1NM_015295.3 linkc.408A>G p.Glu136Glu synonymous_variant Exon 3 of 48 ENST00000320876.11 NP_056110.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMCHD1ENST00000320876.11 linkc.408A>G p.Glu136Glu synonymous_variant Exon 3 of 48 5 NM_015295.3 ENSP00000326603.7
SMCHD1ENST00000688342.1 linkc.408A>G p.Glu136Glu synonymous_variant Exon 3 of 47 ENSP00000508422.1
SMCHD1ENST00000684915.1 linkn.565A>G non_coding_transcript_exon_variant Exon 3 of 14

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000209
AC:
3
AN:
1433982
Hom.:
0
Cov.:
30
AF XY:
0.00000281
AC XY:
2
AN XY:
711004
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32940
American (AMR)
AF:
0.00
AC:
0
AN:
40248
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25504
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38982
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83022
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51890
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5724
European-Non Finnish (NFE)
AF:
0.00000274
AC:
3
AN:
1096284
Other (OTH)
AF:
0.00
AC:
0
AN:
59388
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0628932), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32
Alfa
AF:
0.0000414
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Facioscapulohumeral muscular dystrophy 2 Benign:1
Oct 17, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.44
CADD
Benign
11
DANN
Benign
0.61
PhyloP100
4.0

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

Other links and lift over

dbSNP: rs1057519643; hg19: chr18-2667014; API