rs2276092

Variant names:

• chr18-2707621-G-A
• rs2276092
• NM_015295.3:c.2122G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-2707621-G-A
• chr18-2707621-G-C
• chr18-2707621-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/21 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:5
• Conservation: PhyloP100: 0.306
• Publications: 40 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: 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

ENSG00000266049 (HGNC:):

ACMG classification

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

• 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 VariationId is 260637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SMCHD1	NM_015295.3	c.2122G>A	p.Val708Ile	missense_variant	Exon 16 of 48	ENST00000320876.11	NP_056110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMCHD1	ENST00000320876.11	c.2122G>A	p.Val708Ile	missense_variant	Exon 16 of 48	5	NM_015295.3	ENSP00000326603.7

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

GnomAD2 exomes AF: 0.696 AC: 170285 AN: 244662 AF XY: 0.689

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 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

African (AFR) AF: 0.724 AC: 23927 AN: 33030

American (AMR) AF: 0.790 AC: 34350 AN: 43476

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 16986 AN: 25900

East Asian (EAS) AF: 0.579 AC: 22920 AN: 39556

South Asian (SAS) AF: 0.637 AC: 53889 AN: 84664

European-Finnish (FIN) AF: 0.648 AC: 34482 AN: 53248

Middle Eastern (MID) AF: 0.675 AC: 3864 AN: 5728

European-Non Finnish (NFE) AF: 0.712 AC: 786977 AN: 1104910

Other (OTH) AF: 0.707 AC: 42367 AN: 59942

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

African (AFR) AF: 0.727 AC: 30103 AN: 41388

American (AMR) AF: 0.773 AC: 11803 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2319 AN: 3470

East Asian (EAS) AF: 0.612 AC: 3168 AN: 5174

South Asian (SAS) AF: 0.628 AC: 3028 AN: 4820

European-Finnish (FIN) AF: 0.629 AC: 6621 AN: 10518

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.708 AC: 48109 AN: 67946

Other (OTH) AF: 0.713 AC: 1498 AN: 2102

Alfa AF: 0.707 Hom.: 171752

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Facioscapulohumeral muscular dystrophy 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhinia with choanal atresia and microphthalmia syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.31
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
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

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