22-45344581-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_148674.5(SMC1B):c.3683G>C(p.Ser1228Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,972 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (28 hom.)
• Consequence: SMC1B NM_148674.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.181

Genes affected

SMC1B (HGNC:11112): (structural maintenance of chromosomes 1B) SMC1L2 belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis (3:Revenkova et al., 2001 [PubMed 11564881]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028643906).
• BP6: Variant 22-45344581-C-G is Benign according to our data. Variant chr22-45344581-C-G is described in ClinVar as [Benign]. Clinvar id is 728760.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00116 (176/152338) while in subpopulation EAS AF= 0.0299 (155/5188). AF 95% confidence interval is 0.026. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 174 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMC1B	NM_148674.5	c.3683G>C	p.Ser1228Thr	missense_variant	25/25	ENST00000357450.9
SMC1B	NM_001291501.2	c.3461G>C	p.Ser1154Thr	missense_variant	23/23
SMC1B	XM_011530144.3	c.3560G>C	p.Ser1187Thr	missense_variant	25/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMC1B	ENST00000357450.9	c.3683G>C	p.Ser1228Thr	missense_variant	25/25	5	NM_148674.5	P1
SMC1B	ENST00000404354.3	c.3461G>C	p.Ser1154Thr	missense_variant	23/23	1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152220 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00213 AC: 530 AN: 249102 Hom.: 5 AF XY: 0.00210 AC XY: 284 AN XY: 135206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0285

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.00102 AC: 1493 AN: 1461634 Hom.: 28 Cov.: 29 AF XY: 0.00106 AC XY: 772 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0332

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152338 Hom.: 1 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0299

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.00123

ExAC AF: 0.00221 AC: 267

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.37
Dann	Benign	0.90
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.49	N
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.093
Sift	Benign	0.12	T;D
Sift4G	Benign	0.50	T;T
Vest4		0.068
MVP		0.31
MPC		0.26
ClinPred		0.015	T
GERP RS		1.9
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs148739949; hg19: chr22-45740462; COSMIC: COSV53416312; COSMIC: COSV53416312;