rs2276092

chr18-2707621-G-Achr18-2707621-G-Cchr18-2707621-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_015295.3(SMCHD1):c.2122G>A(p.Val708Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,602,340 control chromosomes in the GnomAD database, including 398,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38247 hom., cov: 30)
  • Exomes 𝑓: 0.70 (360236 hom.)
• Consequence: SMCHD1 NM_015295.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.306

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMCHD1
• BP4: Computational evidence support a benign effect (MetaRNN=7.739487E-7).
• BP6: Variant 18-2707621-G-A is Benign according to our data. Variant chr18-2707621-G-A is described in ClinVar as [Benign]. Clinvar id is 260637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-2707621-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMCHD1	NM_015295.3	c.2122G>A	p.Val708Ile	missense_variant	16/48	ENST00000320876.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMCHD1	ENST00000320876.11	c.2122G>A	p.Val708Ile	missense_variant	16/48	5	NM_015295.3	P2
	ENST00000583546.1	n.371-15741C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107502 AN: 151768 Hom.: 38212 Cov.: 30

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.773

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.712

GnomAD3 exomes AF: 0.696 AC: 170285 AN: 244662 Hom.: 59770 AF XY: 0.689 AC XY: 91433 AN XY: 132610

Gnomad AFR exome AF: 0.722

Gnomad AMR exome AF: 0.796

Gnomad ASJ exome AF: 0.664

Gnomad EAS exome AF: 0.609

Gnomad SAS exome AF: 0.636

Gnomad FIN exome AF: 0.643

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.712

GnomAD4 exome AF: 0.703 AC: 1019762 AN: 1450454 Hom.: 360236 Cov.: 30 AF XY: 0.699 AC XY: 504671 AN XY: 721716

Gnomad4 AFR exome AF: 0.724

Gnomad4 AMR exome AF: 0.790

Gnomad4 ASJ exome AF: 0.656

Gnomad4 EAS exome AF: 0.579

Gnomad4 SAS exome AF: 0.637

Gnomad4 FIN exome AF: 0.648

Gnomad4 NFE exome AF: 0.712

Gnomad4 OTH exome AF: 0.707

GnomAD4 genome AF: 0.708 AC: 107592 AN: 151886 Hom.: 38247 Cov.: 30 AF XY: 0.706 AC XY: 52374 AN XY: 74218

Gnomad4 AFR AF: 0.727

Gnomad4 AMR AF: 0.773

Gnomad4 ASJ AF: 0.668

Gnomad4 EAS AF: 0.612

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.629

Gnomad4 NFE AF: 0.708

Gnomad4 OTH AF: 0.713

Alfa AF: 0.707 Hom.: 93918

Bravo AF: 0.722

TwinsUK AF: 0.729 AC: 2703

ALSPAC AF: 0.709 AC: 2734

ESP6500AA AF: 0.730 AC: 2659

ESP6500EA AF: 0.703 AC: 5737

ExAC AF: 0.694 AC: 83803

Asia WGS AF: 0.654 AC: 2275 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2021

- -

Arrhinia with choanal atresia and microphthalmia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.7
Dann	Benign	0.82
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	7.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.038
Sift	Benign	0.49	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.53
ClinPred		0.00017	T
GERP RS		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs2276092; hg19: chr18-2707619; COSMIC: COSV55253306; COSMIC: COSV55253306;