rs199802471

chr12-49040959-G-Achr12-49040959-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4 BP6_Very_Strong BS2

The NM_003482.4(KMT2D):c.6811C>T(p.Pro2271Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,611,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2271L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 3.04

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.36973906).
• BP6: Variant 12-49040959-G-A is Benign according to our data. Variant chr12-49040959-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49040959-G-A is described in Lovd as [Likely_benign]. Variant chr12-49040959-G-A is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.6811C>T	p.Pro2271Ser	missense_variant	32/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.6811C>T	p.Pro2271Ser	missense_variant	32/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000508 AC: 125 AN: 246068 Hom.: 0 AF XY: 0.000561 AC XY: 75 AN XY: 133612

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000590

Gnomad ASJ exome AF: 0.00112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000692

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000781

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000674 AC: 984 AN: 1458882 Hom.: 1 Cov.: 35 AF XY: 0.000693 AC XY: 503 AN XY: 725614

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000678

Gnomad4 ASJ exome AF: 0.000540

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000685

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000773

Gnomad4 OTH exome AF: 0.000615

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74450

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000624 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000732 AC: 6

ExAC AF: 0.000397 AC: 48

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2018	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Kabuki syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Kabuki syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

KMT2D: BP4 -

KMT2D-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.85
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.71	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D
Polyphen		0.024	B
Vest4		0.70
MVP		0.40
MPC		0.17
ClinPred		0.040	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.094

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: rs199802471; hg19: chr12-49434742; COSMIC: COSV99040275; COSMIC: COSV99040275;