rs34336420

Variant names:

• chr2-10047996-C-T
• rs34336420
• NM_003597.5:c.659C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-10047996-C-T
• chr2-10047996-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003597.5(KLF11):​c.659C>T​(p.Thr220Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,614,082 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (52 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (39 hom.)
• Consequence: KLF11 NM_003597.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:8
• Conservation: PhyloP100: 0.392
• Publications: 31 publications found

Genes affected

KLF11 (HGNC:11811): (KLF transcription factor 11) The protein encoded by this gene is a zinc finger transcription factor that binds to SP1-like sequences in epsilon- and gamma-globin gene promoters. This binding inhibits cell growth and causes apoptosis. Defects in this gene are a cause of maturity-onset diabetes of the young type 7 (MODY7). Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]

KLF11 Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young type 7

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• monogenic diabetes

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.04048261).
• BP6: Variant 2-10047996-C-T is Benign according to our data. Variant chr2-10047996-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 6499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0121 (1842/152306) while in subpopulation AFR AF = 0.0417 (1734/41558). AF 95% confidence interval is 0.0401. There are 52 homozygotes in GnomAd4. There are 868 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1842 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003597.5. 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
	KLF11	NM_003597.5	MANE Select	c.659C>T	p.Thr220Met	missense	Exon 3 of 4	NP_003588.1	O14901-1
	KLF11	NM_001177716.2		c.608C>T	p.Thr203Met	missense	Exon 3 of 4	NP_001171187.1	O14901-2
	KLF11	NM_001177718.2		c.608C>T	p.Thr203Met	missense	Exon 3 of 4	NP_001171189.1	O14901-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLF11	ENST00000305883.6	TSL:1 MANE Select	c.659C>T	p.Thr220Met	missense	Exon 3 of 4	ENSP00000307023.1	O14901-1
	KLF11	ENST00000535335.1	TSL:2	c.608C>T	p.Thr203Met	missense	Exon 3 of 4	ENSP00000442722.1	O14901-2
	KLF11	ENST00000540845.5	TSL:2	c.608C>T	p.Thr203Met	missense	Exon 3 of 4	ENSP00000444690.1	O14901-2

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1830 AN: 152188 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00335 AC: 842 AN: 251388 AF XY: 0.00241

Gnomad AFR exome AF: 0.0457

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00140 AC: 2046 AN: 1461776 Hom.: 39 Cov.: 37 AF XY: 0.00115 AC XY: 836 AN XY: 727210

African (AFR) AF: 0.0453 AC: 1518 AN: 33480

American (AMR) AF: 0.00217 AC: 97 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39700

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000132 AC: 147 AN: 1112000

Other (OTH) AF: 0.00330 AC: 199 AN: 60392

GnomAD4 genome AF: 0.0121 AC: 1842 AN: 152306 Hom.: 52 Cov.: 33 AF XY: 0.0117 AC XY: 868 AN XY: 74460

African (AFR) AF: 0.0417 AC: 1734 AN: 41558

American (AMR) AF: 0.00418 AC: 64 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68024

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00385 Hom.: 18

Bravo AF: 0.0142

ESP6500AA AF: 0.0458 AC: 202

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00421 AC: 511

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
1	-	2	Maturity-onset diabetes of the young type 7 (3)
-	-	1	Monogenic diabetes (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.39
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Benign	0.031	D
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.66
MVP		0.59
MPC		0.022
ClinPred		0.011	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.32
Mutation Taster		=98/2	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: rs34336420; hg19: chr2-10188123; COSMIC: COSV59941457; COSMIC: COSV59941457;