2-17708651-C-T

Variant names:

• chr2-17708651-C-T
• rs6711251
• NM_001142286.2:c.1833G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001142286.2(SMC6):​c.1833G>A​(p.Val611Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,507,630 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: SMC6 NM_001142286.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.97
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-17708651-C-T is Benign according to our data. Variant chr2-17708651-C-T is described in ClinVar as Benign. ClinVar VariationId is 775704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.97 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1653/152130) while in subpopulation AFR AF = 0.0351 (1456/41524). AF 95% confidence interval is 0.0336. There are 28 homozygotes in GnomAd4. There are 812 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1653 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.1833G>A	p.Val611Val	synonymous	Exon 17 of 28	NP_001135758.1	Q96SB8-1
	SMC6	NM_024624.6		c.1833G>A	p.Val611Val	synonymous	Exon 16 of 27	NP_078900.1	A0A2S1ZR87

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMC6	ENST00000448223.7	TSL:1 MANE Select	c.1833G>A	p.Val611Val	synonymous	Exon 17 of 28	ENSP00000404092.2	Q96SB8-1
	SMC6	ENST00000351948.8	TSL:1	c.1833G>A	p.Val611Val	synonymous	Exon 16 of 27	ENSP00000323439.4	Q96SB8-1
	SMC6	ENST00000446852.5	TSL:1	c.1911G>A	p.Val637Val	synonymous	Exon 18 of 20	ENSP00000408644.1	C9JMN1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1648 AN: 152010 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00990

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00265 AC: 536 AN: 202390 AF XY: 0.00177

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000144

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.00352

GnomAD4 exome AF: 0.00110 AC: 1490 AN: 1355500 Hom.: 19 Cov.: 26 AF XY: 0.000983 AC XY: 661 AN XY: 672478

African (AFR) AF: 0.0379 AC: 1099 AN: 29002

American (AMR) AF: 0.00288 AC: 98 AN: 34084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23520

East Asian (EAS) AF: 0.00 AC: 0 AN: 34816

South Asian (SAS) AF: 0.0000440 AC: 3 AN: 68160

European-Finnish (FIN) AF: 0.000301 AC: 15 AN: 49844

Middle Eastern (MID) AF: 0.00222 AC: 12 AN: 5412

European-Non Finnish (NFE) AF: 0.0000910 AC: 96 AN: 1055278

Other (OTH) AF: 0.00302 AC: 167 AN: 55384

GnomAD4 genome AF: 0.0109 AC: 1653 AN: 152130 Hom.: 28 Cov.: 32 AF XY: 0.0109 AC XY: 812 AN XY: 74390

African (AFR) AF: 0.0351 AC: 1456 AN: 41524

American (AMR) AF: 0.00989 AC: 151 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67948

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.00498 Hom.: 8

Bravo AF: 0.0127

Asia WGS AF: 0.00202 AC: 8 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.8
DANN	Benign	0.79
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs6711251; hg19: chr2-17889918;