rs186678728

Variant names:

• chr18-2728602-C-G
• rs186678728
• NM_015295.3:c.2913+6C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015295.3(SMCHD1):​c.2913+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,609,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SMCHD1 NM_015295.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002520
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.25
• Publications: 0 publications found

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

ENSG00000266049 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 18-2728602-C-G is Benign according to our data. Variant chr18-2728602-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00143 (217/152212) while in subpopulation AFR AF = 0.00479 (199/41540). AF 95% confidence interval is 0.00425. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 217 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.2913+6C>G		splice_region intron	N/A	NP_056110.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMCHD1	ENST00000320876.11	TSL:5 MANE Select	c.2913+6C>G		splice_region intron	N/A	ENSP00000326603.7	A6NHR9-1
	SMCHD1	ENST00000939310.1		c.2826+6C>G		splice_region intron	N/A	ENSP00000609369.1
	SMCHD1	ENST00000688342.1		c.2913+6C>G		splice_region intron	N/A	ENSP00000508422.1	A0A8I5KRS9

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00476

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: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000304 AC: 74 AN: 243712 AF XY: 0.000272

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000135 AC: 196 AN: 1456858 Hom.: 0 Cov.: 30 AF XY: 0.000115 AC XY: 83 AN XY: 724526

African (AFR) AF: 0.00467 AC: 155 AN: 33226

American (AMR) AF: 0.000456 AC: 20 AN: 43892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 85348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110030

Other (OTH) AF: 0.000316 AC: 19 AN: 60192

GnomAD4 genome AF: 0.00143 AC: 217 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74416

African (AFR) AF: 0.00479 AC: 199 AN: 41540

American (AMR) AF: 0.000980 AC: 15 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.00164

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Facioscapulohumeral muscular dystrophy 2 (1)
-	-	1	SMCHD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.6
DANN	Benign	0.77
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.032
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

Other links and lift over

dbSNP: rs186678728; hg19: chr18-2728600;