Genetic Variant SMC6:p.Ile721Asn (chr2-17701890-A-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001142286.2(SMC6):c.2162T>A(p.Ile721Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000509 in 1,572,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

SMC6
NM_001142286.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.409

Publications

0 publications found

Variant links:

Genes affected

SMC6 (HGNC:20466): (structural maintenance of chromosomes 6) Enables ubiquitin protein ligase binding activity. Involved in several processes, including cellular senescence; positive regulation of chromosome segregation; and telomere maintenance via recombination. Located in chromosome and nuclear body. Part of Smc5-Smc6 complex. [provided by Alliance of Genome Resources, Apr 2022]

SMC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039952904).

BP6

Variant 2-17701890-A-T is Benign according to our data. Variant chr2-17701890-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3166414.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142286.2. 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
	SMC6	NM_001142286.2	MANE Select	c.2162T>A	p.Ile721Asn	missense	Exon 20 of 28	NP_001135758.1	Q96SB8-1
	SMC6	NM_024624.6		c.2162T>A	p.Ile721Asn	missense	Exon 19 of 27	NP_078900.1	A0A2S1ZR87

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMC6	ENST00000448223.7	TSL:1 MANE Select	c.2162T>A	p.Ile721Asn	missense	Exon 20 of 28	ENSP00000404092.2	Q96SB8-1
SMC6	ENST00000351948.8	TSL:1	c.2162T>A	p.Ile721Asn	missense	Exon 19 of 27	ENSP00000323439.4	Q96SB8-1
SMC6	ENST00000922960.1		c.2240T>A	p.Ile747Asn	missense	Exon 20 of 28	ENSP00000593019.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000884

AC:

AN:

226354

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000423

AC:

AN:

1420094

Hom.:

Cov.:

AF XY:

0.00000707

AC XY:

AN XY:

706800

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31724

American (AMR)

AF:

0.00

AC:

AN:

39962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25276

East Asian (EAS)

AF:

0.00

AC:

AN:

39036

South Asian (SAS)

AF:

0.00

AC:

AN:

81000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5462

European-Non Finnish (NFE)

AF:

0.00000552

AC:

AN:

1086222

Other (OTH)

AF:

0.00

AC:

AN:

58762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.73

CADD

Benign

7.0

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.033

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.35

M_CAP

Benign

0.0039

MetaRNN

Benign

0.040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.79

PhyloP100

-0.41

PrimateAI

Benign

0.39

PROVEAN

Benign

1.4

REVEL

Benign

0.027

Sift

Benign

0.51

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.12

MutPred

0.47

Gain of ubiquitination at K719 (P = 0.0507)

MVP

0.20

MPC

0.49

ClinPred

0.029

GERP RS

-2.7

Varity_R

0.067

gMVP

0.34

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over