18-2705814-C-T

Variant names:

• chr18-2705814-C-T
• rs145755468
• NM_015295.3:c.1956+7C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015295.3(SMCHD1):​c.1956+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,489,544 control chromosomes in the GnomAD database, including 12 homozygotes. 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 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (12 hom.)
• Consequence: SMCHD1 NM_015295.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001359
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.566

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]

ENSG00000266049 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-2705814-C-T is Benign according to our data. Variant chr18-2705814-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2705814-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00198 (301/152118) while in subpopulation AMR AF= 0.00386 (59/15284). AF 95% confidence interval is 0.00307. There are 0 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.1956+7C>T		splice_region_variant, intron_variant	Intron 14 of 47	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.1956+7C>T		splice_region_variant, intron_variant	Intron 14 of 47	5	NM_015295.3	ENSP00000326603.7

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 303 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000568

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00299

Gnomad OTH AF: 0.00672

GnomAD3 exomes AF: 0.00237 AC: 569 AN: 239758 Hom.: 1 AF XY: 0.00237 AC XY: 309 AN XY: 130150

Gnomad AFR exome AF: 0.000330

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000704

Gnomad FIN exome AF: 0.00108

Gnomad NFE exome AF: 0.00386

Gnomad OTH exome AF: 0.00447

GnomAD4 exome AF: 0.00232 AC: 3100 AN: 1337426 Hom.: 12 Cov.: 19 AF XY: 0.00237 AC XY: 1591 AN XY: 671490

Gnomad4 AFR exome AF: 0.000679

Gnomad4 AMR exome AF: 0.00249

Gnomad4 ASJ exome AF: 0.000160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000806

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74358

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000568

Gnomad4 NFE AF: 0.00299

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00291 Hom.: 1

Bravo AF: 0.00247

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Aug 21, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMCHD1: BP4, BS1 -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.83
CADD	Benign	4.3
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0040
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

LitVar

Other links and lift over

dbSNP: rs145755468; hg19: chr18-2705812;